Pulmonary hypertension: Linking inflammation and pulmonary arterial stiffening

Abstract

Pulmonary hypertension (PH) is a progressive disease that arises from multiple etiologies and ultimately leads to right heart failure as the predominant cause of morbidity and mortality. In patients, distinct inflammatory responses are a prominent feature in different types of PH, and various immunomodulatory interventions have been shown to modulate disease development and progression in animal models. Specifically, PH-associated inflammation comprises infiltration of both innate and adaptive immune cells into the vascular wall of the pulmonary vasculature—specifically in pulmonary vascular lesions—as well as increased levels of cytokines and chemokines in circulating blood and in the perivascular tissue of pulmonary arteries (PAs). Previous studies suggest that altered hemodynamic forces cause lung endothelial dysfunction and, in turn, adherence of immune cells and release of inflammatory mediators, while the resulting perivascular inflammation, in turn, promotes vascular remodeling and the progression of PH. As such, a vicious cycle of endothelial activation, inflammation, and vascular remodeling may develop and drive the disease process. PA stiffening constitutes an emerging research area in PH, with relevance in PH diagnostics, prognostics, and as a therapeutic target. With respect to its prognostic value, PA stiffness rivals the well-established measurement of pulmonary vascular resistance as a predictor of disease outcome. Vascular remodeling of the arterial extracellular matrix (ECM) as well as vascular calcification, smooth muscle cell stiffening, vascular wall thickening, and tissue fibrosis contribute to PA stiffening. While associations between inflammation and vascular stiffening are well-established in systemic vascular diseases such as atherosclerosis or the vascular manifestations of systemic sclerosis, a similar connection between inflammatory processes and PA stiffening has so far not been addressed in the context of PH. In this review, we discuss potential links between inflammation and PA stiffening with a specific focus on vascular calcification and ECM remodeling in PH.

Introduction

Pulmonary hypertension (PH) comprises a group of diseases in which the mean pulmonary artery pressure (mPAP) exceeds 25 mmHg at rest according to current guidelines (1). Recently, the 6th World Symposium on PH has recommended to lower this cutoff further to 20 mmHg (2). The World Health Organization (WHO) classifies PH into five groups based on identifiable cause and risk factors (3). Although the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) has entered the stage of targeted therapy, the 5-year survival rate of patients with PAH is still only approximately 50% (4), presumably due to the multifactorial pathophysiological mechanisms of PAH, which evade targeting by a single pharmacological drug, in particular at the advanced disease stage (5). Therefore, identification and therapeutic targeting of common upstream mechanisms that trigger multiple downstream cellular and molecular processes governing pulmonary vascular remodeling in different PH groups remains the ultimate goal for an improved care of PH patients.

Lately, pulmonary perivascular inflammation has gradually gained increased attention as an early common hallmark across different PH groups. In the early stage of the disease, PAH patients and corresponding animal models not only display an accumulation of immune cells such as macrophages (6, 7) and mast cells (8) in their lungs (9), but also have elevated levels of inflammatory mediators in their pulmonary circulation (10, 11) (Figure 1). In most forms of PH, this inflammatory response is predominantly localized to the pulmonary adventitia (7). In fact, changes in the adventitia, which consists of a complex mix of heterogeneous cells, tend to precede those in other vascular compartments and are required for vascular remodeling (12). In PAH, this spatial predilection has been linked to the fact that fibroblasts in the pulmonary adventitia exhibit a pro-inflammatory phenotype with an increased expression of inflammatory mediators that drive the recruitment of innate immune cells (7, 13, 14). The resulting perivascular inflammation is now considered to constitute a critical pathomechanism orchestrating remodeling from the outside-in not only in PH associated with disorders of the immune system, such as connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) (15), but also in other forms of PAH (11, 16) as well as in PH due to left heart disease (PH-LHD) (17). In parallel, the adventitia releases a myriad of factors that regulate differentiation, proliferation, apoptosis, migration, and collagen synthesis by other cells in the vessel wall, while adventitial fibroblasts can transform to myofibroblasts and migrate into the intima through the medial layer (12). As such, it has been proposed that inflammatory processes alter vascular and immune cell metabolism, ultimately enhancing pulmonary artery (PA) remodeling and aggravating PH (Figure 1).

Figure 1

Concomitantly over the past decade, PA stiffening has emerged as an early hallmark, pathomechanism, and predictor of morbidity and mortality in PH (18–20). Vascular stiffening, defined as increased resistance of the arterial wall to deformation during blood influx, is a consequence of pathological vascular remodeling that can occur in both large proximal arteries and small distal arteries and arterioles. The mechanical consequences of these structural changes are decreased compliance in proximal PAs, and increased resistance to blood flow (pulmonary vascular resistance, PVR) in distal PAs (21). PA compliance (PAC) is essential to transform the pulsatile blood flow that enters the large conduit arteries via the Windkessel effect into the nearly laminar flow at the level of the distal pulmonary vascular tree. As such, PAC reduces right ventricular (RV) afterload and maintains near-constant lung perfusion over the cardiac cycle. In line with the impact of PAC for RV function, invasive or non-invasive assessment of PAC (or capacitance) has revealed PA stiffening in PAH patients as a sensitive predictor of pathological RV remodeling and mortality (21–24). It has further been proposed that stiffening of proximal PAs, through elevation of pulse-wave velocity and the shear stress exerted by the blood, promotes injury and remodeling in distal vessels, thus driving the pathology of PH in a positive feed-forward loop (25). Such interdependency between proximal and distal PA regions would predict that pathological remodeling should occur in parallel in large and small vessels. Indeed, work by Stuart R. Reuben first identified a hyperbolic relationship between PAC and PVR (26). The product of PAC × PVR yields the resistance–compliance (RC) time, which is considered to remain almost constant in PH patients of WHO class I (PAH), III (PH due to chronic lung disease), IV (chronic thrombo-embolic PH), or V (PH with unclear multifactorial mechanisms) and independent of medical therapy (27). Interestingly, however, for patients with WHO class II PH (PH due to left heart disease), RC time is reduced, i.e., for any given PVR, the corresponding PAC is lower as compared to PH patients from other causes. Notably, this reduction in RC time is also associated with an increase in RV afterload (27). This interesting finding may indicate distinct pathomechanisms and/or a higher degree of stiffening in proximal PAs in PH patients with underlying left heart disease as compared to other forms of PH; yet, this notion remains to be rigorously tested and mechanistically explored.

Conversely, mechanical communication between proximal PAs and the distal pulmonary vasculature may also promote restoration of pulmonary vascular homeostasis. Evidence of such a reverse remodeling process derives from a few clinical studies in patients with congenital heart disease and PH due to intracardiac left-to-right shunts causing lung overperfusion. In these patients, surgical banding of the PA—performed with the intent to protect the proximal PA from excessive pressure and flow—could successfully improve PH and, in some cases, reverse vascular remodeling in distal arteries (28, 29).

A growing number of studies reporting techniques to estimate stiffness of proximal PAs in vivo show promise for the use of PA stiffness estimates as a prognostic tool in PH. Most commonly, PA stiffness is estimated by calculation of pulmonary arterial capacitance as ratio of stroke volume over pulmonary pulse pressure, assessed by either cardiac catheterization or non-invasively by echocardiography (20, 30–37), or by calculation of a stiffness index as change in PA pressure (again assessed by right heart catheterization) divided by the corresponding change in PA diameter (determined by real-time imaging modalities, such as cardiac magnetic resonance imaging) (18, 38).

Artery stiffening in cardiovascular disease is mainly attributed to remodeling of the extracellular matrix (ECM) and/or calcification within the arterial wall (39–42) (Figure 1). In particular, PAH is characterized by remodeling of the ECM and thickening of all three layers of the PA wall (43), which ultimately reduces arterial compliance. PAs of PAH patients exhibit an increased deposition of interstitial collagen, including collagen I, collagen XIV, and basement membrane-specific collagens, especially collagen IV (43–45). Additionally, increased expression of other ECM proteins such as elastin and fibronectin, or the matricellular ECM protein tenascin-C by dedifferentiated adventitial fibroblasts has been reported in PAH patients (46). Increased production and deposition of ECM constituents in PAs is considered to occur as an adaptive response to increased digestion of medial and basement membrane (BM) ECM by matrix metalloproteinases (MMPs), which have been found to be increased in PAH (47) and IPAH patients (45). The elevated expression of collagens by endothelial cells (ECs), smooth muscle cells (SMCs), and adventitial fibroblasts is associated with increased collagen-cross-linking by lysyl oxidases (LOXs) (48). In addition, proteolytic enzymes also induce degradation of elastic fibers, which are challenging to rebuild despite increased elastin gene expression due to the multicomponent complex 3D structure of these fibers (49–53). As such, PA stiffening emerges as a progressive imbalance of collagen over elastin fiber components in the PA wall.

Vascular stiffening has also been attributed to vascular calcification (40), a pathological deposition of solid minerals within the intima or media of arterial walls (54) (Figure 1). Importantly, pulmonary vascular calcification has been associated with transdifferentiation of SMCs into osteogenic-like lineages, driven by the activity of the pro-osteogenic transcription factor Runt-related transcription factor 2 (RUNX2) (55). As such, increased nuclear expression of RUNX2 in PA SMCs not only activates expression of calcification-related biomineralization genes (56), but also promotes cell proliferation and resistance to apoptosis by activating hypoxia-inducible factor-1α (HIF-1α) (55).

Stiffening of proximal PAs in PAH patients (18, 57) increases pulse pressure and shear stress in the pulmonary vasculature. Of relevance, these alterations in biomechanical forces acting upon the lung vascular wall can induce pro-inflammatory responses in ECs of distal PAs (58, 59) and promote the aggregation of immune cells (58). This includes inflammatory cell recruitment and release of immune-cell-derived cytokines, such as IL-6 (60, 61) and TNF (62) and bioactive enzymes, including MMPs (46), which may, in turn, promote vascular remodeling and stiffening processes, thus establishing a progressive vicious cycle. Such interplay between inflammation-triggered signaling events that, in turn, initiate wound healing processes and ECM remodeling, ultimately culminating in tissue fibrosis and scar formation, is well established in cardiac and systemic vascular diseases (63–65). In PH, however, the cause–effect relationship between inflammatory signaling and vascular stiffening has so far neither clinically nor experimentally been addressed. As such, the present review aims to link known inflammatory responses in PH to processes related to vascular stiffening, namely, ECM remodeling and vascular calcification, identified in either PH or other vascular diseases and vice versa. Proposed links and relevant literature are summarized in Table 1 and will be discussed in detail below. As such, we intend to highlight the potential relevance of a pathophysiological axis between inflammation and PA stiffening, and to incite mechanistic studies to address this conceptual gap in our present understanding of PH.

Inflammation-induced arterial wall thickening and ECM remodeling

PA stiffening and inflammatory responses are both paramount characteristics of PH. While inflammation is commonly associated with PH in both animal models and clinical scenarios, little is known about the role of inflammation in inducing vascular remodeling in PH. Only a limited number of studies have so far addressed the role of inflammation in promoting the production of ECM components (154), namely, collagens (155), fibronectin (156), and tenascin-C (156) in PH. Yet, in other cardiovascular diseases, the connection between inflammation and increased vascular stiffness has been better characterized: here, inflammatory processes have been shown to promote arterial stiffening through a variety of mechanisms, including the induction of endothelial dysfunction and BM stiffening, increased proliferation of SMCs (49)—resulting in arterial wall thickening and reduced compliance—and remodeling and stiffening of the ECM in different segments of the arterial wall.

In PH, elevated pressure and high pulsatile flow as a consequence of reduced vascular compliance can be sensed by ECs of the pulmonary vascular bed. Specifically in hypoxia-induced PH, ECs produce elevated levels of the inflammatory cytokines IL-1β (9) and IL-6 (9, 60), and express increased levels of immune cell adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and P-selectin (9). Concomitantly, other vascular resident cells, such as SMCs and fibroblasts, respond to biomechanical cues by altered secretion of immune factors including inflammatory cytokines such as monocyte chemoattractant protein-1 (MCP-1), stromal cell-derived factor 1, and CCR5 (71) (Table 1). These inflammatory mediators can, in turn, induce PA remodeling and stiffening (9, 71, 157). While the links between increased inflammation and PA remodeling are so far little understood in PH, we will delineate in the following existing connections between key inflammatory signals and vascular stiffening in systemic cardiovascular diseases, with the aim to translate this knowledge into an advanced understanding of the potential role of inflammation in PA stiffening in PH.

Several key inflammatory signals induce PA remodeling by dysregulating the behavior and function of both ECs and SMCs in PH, ultimately leading to arterial wall thickening and stiffening. Among these, IL-6 and TNF were found to be increased in plasma, lung, pulmonary arteries and veins, as well as in PA ECs in both patients and animal models of various PH groups (Table 1). In PAH patients (60) and in PH-LHD rat models (61, 81), IL-6 contributes to PA remodeling by inducing medial wall thickening via SMC proliferation and muscularization of the distal pulmonary arterial tree due to migration of SMCs into precapillary arterioles (60, 61, 81) (Table 2; Figure 2), potentially affecting arterial compliance by increased wall thickening. In the pulmonary adventitia, fibroblasts activate recruited macrophages through paracrine IL-6 signaling, initiating a pro-inflammatory and pro-fibrotic phenotype that is associated with an increased inflammatory response and vascular remodeling in PH (7). Notably, IL-6 is a sensitive marker for systemic inflammation in cardiovascular disease (60, 88). In rheumatoid arthritis (164) and acute ischemic stroke (165), elevated levels of IL-6 in patient serum were associated with aortic stiffening as estimated by pulse-wave velocity, which could be significantly reduced by therapeutic infusions of the anti-IL-6 receptor antibody tocilizumab (164).

Figure 2

Similarly, elevated TNF in rodent models of PAH and PH-LHD has been shown to result in increased PA EC and SMC proliferation and medial wall thickening (61, 166), which have been attributed to suppressed BMPR-II signaling in PAH (166). Due to its effects on SMC hyperplasia, TNF may also promote PA stiffening in PH; however, direct correlations between TNF levels and PA stiffness in PH have yet to be established. In other cardiovascular and inflammatory diseases, e.g., arteriosclerosis, TNF is an established key mediator of vascular remodeling (61, 62). Patients with inflammatory artheropathies, namely, rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, who received anti-TNF treatment with either adalimumab, etanercept, or infliximab, showed a reduction in aortic stiffness as assessed by pulse-wave velocity and augmentation index as compared to untreated controls (107, 167). Hence, pharmacological inhibition of inflammatory mediators such as IL-6 and TNF in PH could potentially reduce pulmonary vascular cell proliferation and PA thickening and may therefore present a targeted therapy for PA stiffening.

Furthermore, pro-inflammatory mediators can induce vascular stiffening in cardiovascular diseases by increased production of ECM components, namely, fibrillar and non-fibrillar collagens and fibronectin by resident vascular cells (168). After myocardial infarction as well as in ischemic and non-ischemic heart failure, pro-inflammatory mediators such as TGF-β (74, 169) and IL-1β (170) induce the conversion of fibroblasts into myofibroblasts, which can produce abundant ECM proteins (168) (Tables 1, 2; Figure 2). In PH, adventitial myofibroblasts contribute to PA remodeling and stiffening (46) via the production of structural ECM components such as collagens, elastin, fibronectin, and dynamic ECM constituents, including tenascin-C and osteopontin (43, 46, 74) (Table 2; Figure 2). Tenascin-C and osteopontin, in turn, increase fibroblast and SMC proliferation, contributing to myofibroblast conversion and medial thickening, and therefore vascular stiffening (43, 46, 171) (Figure 2). Activated macrophages recruited to the pulmonary adventitia may express ECM proteins such as collagen type I, thereby contributing to ECM stiffening in PH (172). In animal models of MCT-induced PH, NADPH oxidase 4 (Nox4) has also been found to be upregulated in the pulmonary adventitia, where it promotes TGF-β-mediated expression of matrix collagens by adventitial fibroblasts and, as such, ECM stiffening (172). Similarly, collagen deposition by resident fibroblasts into the adventitia was also found to be increased in an animal model of chronic hypoxic PH and resulted in a thicker and stiffer arterial wall (172–174). In order to form insoluble rigid fibers, excessive fibrillar collagens are then further cross-linked by cross-linking enzymes (43, 175). Specifically, elevated expression of LOX in SMCs and lysyl oxidase-like enzyme (LOXL) expression in adventitial fibroblasts leads to increased collagen cross-linking and PA stiffening in PAH (176). Moreover, adventitial fibroblasts per se exhibit a pro-inflammatory phenotype in PH, including the recruitment and activation of adventitial macrophages (7) and production of pro-inflammatory markers, such as the chemokines MCP-1, SDF-1, RANTES/CCR5, CCR7, CXCR4, and the co-stimulatory molecules CD40 and CD40L (7, 71). This secretory activity can, in turn, create another feedback loop that triggers further inflammation and, hence, ECM remodeling.

Apart from elevated levels of circulating inflammatory mediators, increased mPAP in PH also induces activation of the pro-inflammatory NF-κB signaling pathway in PA ECs and SMCs (58, 133, 157) (Figure 2). Based on studies in systemic cardiovascular diseases, such activation of NF-κB emerges as a potentially important step in PA stiffening. As such, nuclear NF-κB was shown to increase the expression of aortic collagen type I in a murine model of type 2 diabetes, resulting in aortic stiffening as measured ex vivo by pressure myography (177). Interestingly, these effects were mediated by an NF-κB-dependent overexpression of RUNX2, a key transcription factor relevant not only for ECM remodeling [through increased expression of ECM collagens by SMCs (177)], but also in the context of vascular calcification (55, 177) (as discussed below) (Figure 2). It may be speculated that activation of NF-κB could exhibit similar effects in PH, thus contributing to PA stiffening through ECM remodeling and vascular calcification.

Inflammation-induced overproduction of ECM components in cardiovascular diseases is rivaled by elevated proteolytic ECM degradation via a parallel increase in MMPs (46). In PH, activated macrophages and myofibroblasts in the adventitia secrete MMPs, specifically MMP-2 (154, 162), MMP-9 (6, 162), MMP-10 (47), and MMP-19 (6, 154), while tissue inhibitors of metalloproteinases (TIMPs) appear downregulated (46, 162) (Table 2; Figure 2). MMP-2 (50) and MMP-9 (49) degrade elastin, thereby decreasing vessel compliance, resulting in arterial stiffening (49–52). Furthermore, degradation of elastic fibers and other ECM components such as BM collagens, interstitial collagens, fibronectin, and several proteoglycans by MMPs, facilitates migration of adventitial fibroblasts and myofibroblasts into the media and intima, which, in turn, promotes PA stiffening and vascular stenosis (46, 154) (Table 2). Similarly, neointimal formation via increased proliferation and migration of SMC from the media into the intimal regions of the arterial wall is likewise facilitated by MMP-regulated ECM degradation (52, 178) and promotes vascular stenosis and stiffening (178). Products of ECM proteolysis—the matrikines [recently reviewed in detail by Mutgan et al. (179)]—can, in turn, serve as pro-inflammatory mediators, which accentuate inflammation and may, as such, create another positive feedback loop (43). Furthermore, ECM degradation allows for circulating serum factors to enter the media and stimulate serine elastase production by SMCs (178). These serine elastases aid elastin degradation and the release of activated growth factors, such as fibroblast growth factor (FGF) and TGF-β that, in turn, increase collagen, fibronectin, and tenascin-C production by SMCs and fibroblasts (43)—again furthering PA stiffening (Table 2). In other cardiovascular diseases such as ischemic heart failure, immune cells like macrophages, lymphocytes, and mast cells secrete MMPs that remodel the vascular and cardiac ECM in response to mechanical stress (168). In arteriosclerosis, elevated levels of both MMP-2 and MMP-9 were associated with increased arterial stiffness and cardiovascular disease risk, which has been attributed to their ability to degrade the elastic laminae in arteries (180, 181). Accordingly, MMP-2 knockdown reduces arterial stiffening of carotid arteries in mice by decreasing elastin degradation in the tissue (182).

As such, activation of immune cells and inflammatory pathways, and arterial wall thickening and ECM remodeling may reciprocally stimulate each other. Targeting inflammatory processes in cardiovascular diseases, for example, aortic aneurysms, has shown beneficial effects on key mechanisms of ECM remodeling such as elastin degradation, MMP expression, and macrophage infiltration (183). As such, a better understanding of the specific players and molecular pathways involved in this mutual interaction may reveal novel and potentially personalized targets for future PH therapy.

Pulmonary arterial calcification and inflammation

Biologically induced mineralization is an integral part of human physiology and tissue homeostasis that involves extracellular and intracellular mechanisms to direct the nucleation, growth, and location of the deposited minerals. In disease conditions, these processes may become dysbalanced due to changes in the local or global calcium milieu, DNA damage, endoplasmic reticulum stress, oxidative stress, or metabolic disorders—i.e., processes that are frequently associated with inflammatory responses—and ultimately result in pathological tissue or blood vessel calcification (184, 185). Mechanistically, these factors lead to (or are accompanied by) phenotypic conversion of various cell types into osteoprogenitor cells via de novo or increased expression, respectively, of the potent transcription activator RUNX2, which triggers the expression of downstream calcification-promoting proteins such as alkaline phosphatase (186–188). In comparison to systemic arteries, vascular calcification of the PA is scarcely addressed, yet it is actually a common feature in patients with severe prolonged PH (189), advanced PH, and PH with chronic renal failure (190) or end-stage renal disease (191). In fact, detection of peripheral PA calcification by computed tomography (CT) (192) predicts long-term outcome in PH (193) and in patients with atrial septal defect and Eisenmenger’s syndrome (194).

In the context of PAH, a critical role in the regulation of PA calcification has been attributed to a microRNA-204-dependent upregulation of RUNX2 that, in turn, activates HIF-1α, leading to PA SMC hyperproliferation, resistance to apoptosis, and subsequent transdifferentiation into osteoblast-like cells (55). A second study reported that hypoxia-induced circular RNA CDR1 promotes osteogenic transdifferentiation of human PA SMCs by sponging microRNA-7-5p, and consequently upregulating its downstream targets calcium/calmodulin-dependent kinase II-delta (CAMK2D) and calponin 3 (CNN3) (195). Third, PA calcification has been linked to hypoxia, in that hypoxia decreases the expression of serine protease granzyme B stored in the granules of T lymphocytes and natural killer cells, which inhibits store-operated calcium channels (SOCCs) as the main source of calcium mineral by attenuating non-canonical Wnt signals in SMCs, thus increasing calcification of the PA (141). Independent of the underlying pathway, calcification ultimately increases vascular stiffness and reduces the compliance of the pulmonary arterial wall, which is a manifestation of poor prognosis in PH (21).

In the systemic vasculature, inflammatory signals—as seen in PH—have been shown to regulate vascular calcification processes. Specifically, TNF promotes osteogenic differentiation and calcification of bovine aortic SMCs by inducing the expression of osteoblast markers, such as osteoblast-specific factor 2 (Osf2), activator protein 1 (AP1), and cAMP-responsive element-binding protein (CREB) via activation of cAMP signaling (104). Likewise, treatment of aortic SMCs with IL-1β or IL-6 caused a dose-dependent increase in alkaline phosphatase activity and increased cell mineralization in vitro (196). Interestingly, expression of the inflammatory cytokines IL-6, TNF, and MCP-1 is epigenetically regulated in various tissues by bromodomain protein 4 (BRD4) (86), which modulates the chromatin landscape and activates gene expression by scaffolding transcription factors at gene promoters and/or superenhancers. Notably, BRD4 is upregulated in PA SMCs of PAH patients and in lungs or distal PAs of rat PH models, and is posttranscriptionally regulated by microRNA-204 (87), which is concomitantly involved in PA calcification (55), providing for an additional epigenetic link between inflammation and vascular calcification. More importantly, the RUNX2 gene promoter has been shown to be under direct control of BRD4 during osteoblast differentiation (197) as well as in cancer (198), suggesting that BRD4 may serve as a “master-regulator” of both inflammation and vascular calcification in parallel. In line with this notion, BRD4 inhibition attenuated pulmonary and coronary artery remodeling in experimental PH, and this protective effect was associated with reduced levels of IL-6 and MCP-1 (199, 200).

Although studies linking calcification and inflammation in PH are scarce, cytokines have been implicated in the regulation of calcification in the extra-pulmonary vasculature. Importantly, vascular calcification also seems to be closely interconnected with ECM remodeling and stiffening (201), as SMC mineralization directly correlates with the production of collagen I and fibronectin and elastin degradation, while the latter forms scaffolds for calcium incorporation (201–203). These findings suggest that upstream inflammation may also promote vascular calcification through ECM remodeling.

Pulmonary arterial endothelial-to-mesenchymal transition and inflammation

While our interrogation of vascular calcification processes has at large focused on SMCs, it is important to keep in mind that ECs are also involved. In various cardiovascular diseases, ECs lose their characteristic morphology and undergo a shift toward a mesenchymal phenotype (204), a process that is termed endothelial-to-mesenchymal transition (EndoMT) and that is notably modulated by inflammation. Specifically, inflammatory cytokines such as IL-1β or TNF have been shown to induce EndoMT in PA ECs. In turn, these EndoMT cells start to secrete inflammatory cytokines including IL-4, IL-6, IL-8, IL-13, and TNF at much higher concentrations as compared to normal PA ECs (205), thus establishing a potentially vicious feed-forward loop. In line with the notion of inflammation-driven EndoMT in PH, activation of the pro-inflammatory NF-κB signaling pathway in a mouse model of monocrotaline (MCT)-induced PH was found to upregulate miR-130a, which induced loss of bone morphogenetic protein receptor type 2 (BMPR2), increased expression of High Mobility Group AT-hook 1 (HMGA1), and ultimately EndoMT in lung microvascular ECs (206). It is important to highlight that although EndoMT has been extensively documented in pulmonary and systemic ECs exposed to inflammatory mediators in vitro, the extent and relevance of EndoMT in vivo in recent studies using lineage tracing technologies remains controversial: By use of double transgenic mice stably expressing green fluorescent protein (GFP) in all ECs, Suzuki and colleagues detected GFP in 14.3 ± 1.8% of mesenchymal (CD144^-CD45^-CD326^-) cells, indicating substantial EndoMT (207). Similarly, endothelial lineage tracing using transgenic vascular endothelial-cadherin Cre recombinase or Tie-2 Cre mice intercrossed with mTomato/mGreen fluorescent protein double-fluorescent Cre reporter mice revealed abundant endothelial lineage-marked cells in the neointima where they expressed smooth muscle α-actin and smooth muscle myosin heavy chain following induction of PH by monocrotaline pyrrole (208). Yet, a recent lineage tracing study in chronic hypoxia and allergen-induced models of lung vascular remodeling showed retention of endothelial lineage-specific marker expression profiles without any indication of cell-type conversion (209). Notably, the recognition of limited or partial EndoMT does not necessarily conflict with its potential functional relevance in PA stiffening, but simply suggests that this relevance may potentially relate more to the release of proliferative, hypertrophic, and profibrotic signals—i.e., mediators of processes that will ultimately promote PA stiffness—by partial EndoMT cells rather than to the actual generation of significant mesenchymal cell mass via this mechanism. Indeed, a similar role is increasingly recognized for epithelial–mesenchymal transition in tissue fibrosis (210).

Over and above that, EndoMT may link inflammation to vascular calcification and, thus, PA stiffening in PH. Specifically, studies in aortic ECs show that inflammatory cytokines such as TNF and IL-1β modulate EndoMT and downregulate the expression of BMPR2 and JNK signaling, thereby sensitizing ECs for BMP9-induced osteogenic differentiation that culminates in mineralization (141). Similar regulatory mechanisms may drive PA EC calcification in different types of PH, and PAH patients with BMPR2 mutations or BMP signaling pathway impairments (104) would be expected to be specifically vulnerable in this scenario given the association of impaired BMPR2 signaling with EndoMT (211). Lineage tracing studies in the systemic circulation support a role for EndoMT in vascular calcification, showing, e.g., that a subset of endocardial cells can undergo endocardial-to-mesenchymal transition resulting in calcification of mouse and human cardiac valves (212) or that vascular ECs can transition into osteogenic cells (213), which can be prevented by inhibition of glycogen synthase kinase 3 (GSK3) (214). The role of EndoMT (or partial EndoMT) in vascular calcification in the pulmonary circulation and in the contact of PH has, however, so far not been addressed.

Potential clinical relevance

While current PH therapies (i.e., prostacyclins, phosphodiesterase inhibitors, calcium channel blockers, endothelin receptor antagonists, or soluble guanylate cyclase stimulators) focus primarily on alleviating vasoconstriction as a symptomatic approach (215), the long-term therapeutic goal is to shift towards targeting mechanisms of disease onset and progression, including vascular remodeling and inflammation (215). In this regard, targeting the immune–PA stiffening axis may present a particularly promising strategy in light of the predictive and pathomechanistic role of PA stiffening in PH, and the armamentarium of immunomodulatory therapies already in clinical use or in development. In the systemic circulation, anti-inflammatory therapies have shown promise to reduce arterial stiffening in inflammatory artheropathies such as rheumatoid or psoriatic arthritis (167). Specifically, TNF antagonists, such as adalimumab, etanercept, or infliximab, represent established anti-inflammatory therapies in (auto-)immune conditions (216) that have explicitly lowered aortic stiffness in patients with inflammatory artheropathies (107, 167).

As such, immunomodulatory treatments are increasingly considered as potential therapeutic strategies for the treatment of PH. Yet, despite promising findings in preclinical models (8, 146, 215, 217), results from clinical trials have so far shown only modest benefit (149, 218, 219), thus stressing the need for more personalized approaches. Given the discussed link between immune responses, ECM remodeling, and vascular calcification, PA stiffness may present a promising biomarker to identify and monitor patients who may profit from immunomodulatory therapies; yet, assessment of PA stiffness in clinical trials is presently rare. Preclinical models, however, highlight the potential promise of anti-inflammatory therapies to target PA stiffness: For example, inhibition of carbonic anhydrases by acetazolamide or ammonium chloride (NH₄Cl) as a potential treatment for inflammation in PH was able to prevent SMC dedifferentiation and proliferation in a Sugen5416/hypoxia rat model (220). Other anti-inflammatory therapies, such as treatment with resveratrol, were similarly able to prevent PA remodeling and stiffening in chronic hypoxic rats (215), while inhibitors of the renin–angiotensin system such as captopril or losartan reduced the production of ECM components including interstitial collagen and the expression of MMP-2 and MMP-9 in PAH, thereby attenuating PA stiffening (215). Hence, targeting inflammation with a specific focus on PA stiffness may provide for a pathomechanism-based and individualized therapy to treat PH—a notion that should be considered and, ideally, may be tested in appropriate preclinical and clinical trials.

Funding

WK was supported by grants from the German Research Foundation (CRC 1470, A04; KU1218/12-1) and the German Center for Cardiovascular Research partner site Berlin, CK was supported by the German Centre for Cardiovascular Research partner site Berlin and by the German Ministry of Education and Research (BMBF), NNV was supported by the Doctoral Scholarship from the German Centre for Cardiovascular Research and the German Cardiology Association (DGK), MK was supported by the German Foundation for Heart Research (F23/20), and S-FL and QL were supported by the China Scholarship Council (No. 202008350142 and No.202108080221).

Acknowledgments

Parts of the figures were generated with the help of BioRender.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1

  SimonneauGMontaniDCelermajerDSDentonCPGatzoulisMAKrowkaMet al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J (2019) 53(1):1801913. doi: 10.1183/13993003.01913-2018

  • CrossRef
  • Google Scholar
  • View reference in article

• 2

  CondonDFNickelNPAndersonRMirzaSde Jesus PerezVA. The 6th world symposium on pulmonary hypertension: What's old is new. F1000Res (2019) 8:F1000 Faculty Rev–888. doi: 10.12688/f1000research.18811.1

  • CrossRef
  • Google Scholar
  • View reference in article

• 3

  SimonneauGRobbinsIMBeghettiMChannickRNDelcroixMDentonCPet al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol (2009) 54:S43–54. doi: 10.1016/j.jacc.2009.04.012

  • CrossRef
  • Google Scholar
  • View reference in article

• 4

  GalieNHumbertMVachieryJLGibbsSLangITorbickiAet al. ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): Endorsed by: Association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT). Eur Respir J (2015) 46:903–75. doi: 10.1183/13993003.01032-2015

  • CrossRef
  • Google Scholar
  • View reference in article

• 5

  LanNSHMassamBDKulkarniSSLangCC. Pulmonary arterial hypertension: Pathophysiology and treatment. Diseases (2018) 6 (2):38. doi: 10.3390/diseases6020038

  • CrossRef
  • Google Scholar
  • View reference in article

• 6

  SavaiRPullamsettiSSKolbeJBieniekEVoswinckelRFinkLet al. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med (2012) 186:897–908. doi: 10.1164/rccm.201202-0335OC

  • CrossRef
  • Google Scholar
  • View reference in article

• 7

  El KasmiKCPuglieseSCRiddleSRPothJMAndersonALFridMGet al. Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension. J Immunol (2014) 193:597–609. doi: 10.4049/jimmunol.1303048

  • CrossRef
  • Google Scholar
  • View reference in article

• 8

  BreitlingSHuiZZabiniDHuYHoffmannJGoldenbergNMet al. The mast cell-b cell axis in lung vascular remodeling and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol (2017) 312:L710–21. doi: 10.1152/ajplung.00311.2016

  • CrossRef
  • Google Scholar
  • View reference in article

• 9

  PuglieseSCPothJMFiniMAOlschewskiAEl KasmiKCStenmarkKR. The role of inflammation in hypoxic pulmonary hypertension: From cellular mechanisms to clinical phenotypes. Am J Physiol Lung Cell Mol Physiol (2015) 308:L229–252. doi: 10.1152/ajplung.00238.2014

  • CrossRef
  • Google Scholar
  • View reference in article

• 10

  SoonEHolmesAMTreacyCMDoughtyNJSouthgateLMachadoRDet al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation (2010) 122:920–7. doi: 10.1161/CIRCULATIONAHA.109.933762

  • CrossRef
  • Google Scholar
  • View reference in article

• 11

  RabinovitchMGuignabertCHumbertMNicollsMR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res (2014) 115:165–75. doi: 10.1161/CIRCRESAHA.113.301141

  • CrossRef
  • Google Scholar
  • View reference in article

• 12

  SpiekerkoetterEGoncharovaEAGuignabertCStenmarkKKwapiszewskaGRabinovitchMet al. Hot topics in the mechanisms of pulmonary arterial hypertension disease: Cancer-like pathobiology, the role of the adventitia, systemic involvement, and right ventricular failure. Pulm Circ (2019) 9:2045894019889775. doi: 10.1177/2045894019889775

  • CrossRef
  • Google Scholar
  • View reference in article

• 13

  KueblerWMBonnetSTabuchiA. Inflammation and autoimmunity in pulmonary hypertension: Is there a role for endothelial adhesion molecules? (2017 grover conference series). Pulm Circ (2018) 8:2045893218757596. doi: 10.1177/2045893218757596

  • CrossRef
  • Google Scholar
  • View reference in article

• 14

  HuYChiLKueblerWMGoldenbergNM. Perivascular inflammation in pulmonary arterial hypertension. Cells (2020) 9 (11):2338. doi: 10.3390/cells9112338

  • CrossRef
  • Google Scholar
  • View reference in article

• 15

  SasakiNKamatakiASawaiT. A histopathological study of pulmonary hypertension in connective tissue disease. Allergol Int (2011) 60:411–7. doi: 10.2332/allergolint.11-RAI-0337

  • CrossRef
  • Google Scholar
  • View reference in article

• 16

  HumbertMMontiGBrenotFSitbonOPortierAGrangeot-KerosLet al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med (1995) 151:1628–31. doi: 10.1164/ajrccm.151.5.7735624

  • CrossRef
  • Google Scholar
  • View reference in article

• 17

  BreitlingSRavindranKGoldenbergNMKueblerWM. The pathophysiology of pulmonary hypertension in left heart disease. Am J Physiol Lung Cell Mol Physiol (2015) 309:L924–941. doi: 10.1152/ajplung.00146.2015

  • CrossRef
  • Google Scholar
  • View reference in article

• 18

  GanCTLankhaarJWWesterhofNMarcusJTBeckerATwiskJWet al. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest (2007) 132:1906–12. doi: 10.1378/chest.07-1246

  • CrossRef
  • Google Scholar
  • View reference in article

• 19

  Agoston-ColdeaLLupuSMocanT. Pulmonary artery stiffness by cardiac magnetic resonance imaging predicts major adverse cardiovascular events in patients with chronic obstructive pulmonary disease. Sci Rep (2018) 8:14447. doi: 10.1038/s41598-018-32784-6

  • CrossRef
  • Google Scholar
  • View reference in article

• 20

  Al-NaamaniNPrestonIRPaulusJKHillNSRobertsKE. Pulmonary arterial capacitance is an important predictor of mortality in heart failure with a preserved ejection fraction. JACC Heart Fail (2015) 3:467–74. doi: 10.1016/j.jchf.2015.01.013

  • CrossRef
  • Google Scholar
  • View reference in article

• 21

  WangZCheslerNC. Pulmonary vascular wall stiffness: An important contributor to the increased right ventricular afterload with pulmonary hypertension. Pulm Circ (2011) 1:212–23. doi: 10.4103/2045-8932.83453

  • CrossRef
  • Google Scholar
  • View reference in article

• 22

  PapolosATisonGHMayfieldJVastiEDeMarcoT. Echocardiographic assessment of pulmonary arterial capacitance predicts mortality in pulmonary hypertension. J Cardiol (2021) 77:279–84. doi: 10.1016/j.jjcc.2020.10.006

  • CrossRef
  • Google Scholar
  • View reference in article

• 23

  SugimotoKYoshihisaANakazatoKJinYSuzukiSYokokawaTet al. Pulmonary arterial capacitance predicts cardiac events in pulmonary hypertension due to left heart disease. PloS One (2016) 11:e0165603. doi: 10.1371/journal.pone.0165603

  • CrossRef
  • Google Scholar
  • View reference in article

• 24

  FriedbergMKFeinsteinJARosenthalDN. Noninvasive assessment of pulmonary arterial capacitance by echocardiography. J Am Soc Echocardiogr (2007) 20:186–90. doi: 10.1016/j.echo.2006.08.009

  • CrossRef
  • Google Scholar
  • View reference in article

• 25

  DieffenbachPBMaracleMTschumperlinDJFredenburghLE. Mechanobiological feedback in pulmonary vascular disease. Front Physiol (2018) 9:951. doi: 10.3389/fphys.2018.00951

  • CrossRef
  • Google Scholar
  • View reference in article

• 26

  ReubenSR. Compliance of the human pulmonary arterial system in disease. Circ Res (1971) 29:40–50. doi: 10.1161/01.RES.29.1.40

  • CrossRef
  • Google Scholar
  • View reference in article

• 27

  TedfordRJHassounPMMathaiSCGirgisRERussellSDThiemannDRet al. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation (2012) 125:289–97. doi: 10.1161/CIRCULATIONAHA.111.051540

  • CrossRef
  • Google Scholar
  • View reference in article

• 28

  LinMTChenYSHuangSCChiuHHChiuSNChenCAet al. Alternative approach for selected severe pulmonary hypertension of congenital heart defect without initial correction–palliative surgical treatment. Int J Cardiol (2011) 151:313–7. doi: 10.1016/j.ijcard.2010.05.067

  • CrossRef
  • Google Scholar
  • View reference in article

• 29

  WagenvoortCAWagenvoortNDraulans-NoeY. Reversibility of plexogenic pulmonary arteriopathy following banding of the pulmonary artery. J Thorac Cardiovasc Surg (1984) 87:876–86. doi: 10.1016/S0022-5223(19)38415-6

  • CrossRef
  • Google Scholar
  • View reference in article

• 30

  ChoJYKimKH. Evaluation of arterial stiffness by echocardiography: Methodological aspects. Chonnam Med J (2016) 52:101–6. doi: 10.4068/cmj.2016.52.2.101

  • CrossRef
  • Google Scholar
  • View reference in article

• 31

  ChengXLHeJGLiuZHGuQNiXHZhaoZHet al. Pulmonary vascular capacitance is associated with vasoreactivity and long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Lung (2016) 194:613–8. doi: 10.1007/s00408-016-9905-0

  • CrossRef
  • Google Scholar
  • View reference in article

• 32

  ShafieDDohaeiAAminATaghaviSNaderiN. Pulmonary vascular capacitance as a predictor of vasoreactivity in idiopathic pulmonary arterial hypertension tested by adenosine. Res Cardiovasc Med (2015) 4(4):e28945. doi: 10.5812/cardiovascmed.28945

  • CrossRef
  • Google Scholar
  • View reference in article

• 33

  SajanIManlhiotCReyesJMcCrindleBWHumplTFriedbergMK. Pulmonary arterial capacitance in children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease: relation to pulmonary vascular resistance, exercise capacity, and survival. Am Heart J (2011) 162:562–8. doi: 10.1016/j.ahj.2011.06.014

  • CrossRef
  • Google Scholar
  • View reference in article

• 34

  PellegriniPRossiAPasottiMRaineriCCicoiraMBonapaceSet al. Prognostic relevance of pulmonary arterial compliance in patients with chronic heart failure. Chest (2014) 145:1064–70. doi: 10.1378/chest.13-1510

  • CrossRef
  • Google Scholar
  • View reference in article

• 35

  DupontMMullensWSkouriHNAbrahamsZWuYTaylorDOet al. Prognostic role of pulmonary arterial capacitance in advanced heart failure. Circ Heart Fail (2012) 5:778–85. doi: 10.1161/CIRCHEARTFAILURE.112.968511

  • CrossRef
  • Google Scholar
  • View reference in article

• 36

  DraguRRisplerSHabibMSholyHHammermanHGalieNet al. Pulmonary arterial capacitance in patients with heart failure and reactive pulmonary hypertension. Eur J Heart Fail (2015) 17:74–80. doi: 10.1002/ejhf.192

  • CrossRef
  • Google Scholar
  • View reference in article

• 37

  SaitoYOhtaniTKiokaHOnishiTTsukamotoYNakamotoKet al. Clinical significance of pulmonary arterial capacitance calculated by echocardiography in patients with advanced heart failure. Circ J (2017) 81:1871–8. doi: 10.1253/circj.CJ-16-1318

  • CrossRef
  • Google Scholar
  • View reference in article

• 38

  SanzJKariisaMDellegrottaglieSPrat-GonzalezSGarciaMJFusterVet al. Evaluation of pulmonary artery stiffness in pulmonary hypertension with cardiac magnetic resonance. JACC Cardiovasc Imaging (2009) 2:286–95. doi: 10.1016/j.jcmg.2008.08.007

  • CrossRef
  • Google Scholar
  • View reference in article

• 39

  BotneyMDKaiserLRCooperJDMechamRPParghiDRobyJet al. Extracellular matrix protein gene expression in atherosclerotic hypertensive pulmonary arteries. Am J Pathol (1992) 140:357–64.

  • Google Scholar
  • View reference in article

• 40

  KohnJCLampiMCReinhart-KingCA. Age-related vascular stiffening: Causes and consequences. Front Genet (2015) 6:112. doi: 10.3389/fgene.2015.00112

  • CrossRef
  • Google Scholar
  • View reference in article

• 41

  WagenseilJEMechamRP. Vascular extracellular matrix and arterial mechanics. Physiol Rev (2009) 89:957–89. doi: 10.1152/physrev.00041.2008

  • CrossRef
  • Google Scholar
  • View reference in article

• 42

  WagenseilJEMechamRP. Elastin in large artery stiffness and hypertension. J Cardiovasc Transl Res (2012) 5:264–73. doi: 10.1007/s12265-012-9349-8

  • CrossRef
  • Google Scholar
  • View reference in article

• 43

  ThenappanTChanSYWeirEK. Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol (2018) 315:H1322–31. doi: 10.1152/ajpheart.00136.2018

  • CrossRef
  • Google Scholar
  • View reference in article

• 44

  BotneyMDLiptayMJKaiserLRCooperJDParksWCMechamRP. Active collagen synthesis by pulmonary arteries in human primary pulmonary hypertension. Am J Pathol (1993) 143:121–9.

  • Google Scholar
  • View reference in article

• 45

  HoffmannJMarshLMPieperMStacherEGhanimBKovacsGet al. Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients. Am J Physiol Lung Cell Mol Physiol (2015) 308:L1002–1013. doi: 10.1152/ajplung.00383.2014

  • CrossRef
  • Google Scholar
  • View reference in article

• 46

  StenmarkKRYeagerMEEl KasmiKCNozik-GrayckEGerasimovskayaEVLiMet al. The adventitia: Essential regulator of vascular wall structure and function. Annu Rev Physiol (2013) 75:23–47. doi: 10.1146/annurev-physiol-030212-183802

  • CrossRef
  • Google Scholar
  • View reference in article

• 47

  ChiPLChengCCHungCCWangMTLiuHYKeMWet al. MMP-10 from M1 macrophages promotes pulmonary vascular remodeling and pulmonary arterial hypertension. Int J Biol Sci (2022) 18:331–48. doi: 10.7150/ijbs.66472

  • CrossRef
  • Google Scholar
  • View reference in article

• 48

  BerteroTOldhamWMCottrillKAPisanoSVanderpoolRRYuQet al. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest (2016) 126:3313–35. doi: 10.1172/JCI86387

  • CrossRef
  • Google Scholar
  • View reference in article

• 49

  McEnieryCMWilkinsonIB. Large Artery stiffness and inflammation. J Hum Hypertens (2005) 19:507–9. doi: 10.1038/sj.jhh.1001814

  • CrossRef
  • Google Scholar
  • View reference in article

• 50

  HardyEHardy-SosaAFernandez-PatronC. MMP-2: Is too low as bad as too high in the cardiovascular system? Am J Physiol Heart Circ Physiol (2018) 315:H1332–40. doi: 10.1152/ajpheart.00198.2018

  • CrossRef
  • Google Scholar
  • View reference in article

• 51

  LoffekSSchillingOFranzkeCW. Series "matrix metalloproteinases in lung health and disease": Biological role of matrix metalloproteinases: A critical balance. Eur Respir J (2011) 38:191–208. doi: 10.1183/09031936.00146510

  • CrossRef
  • Google Scholar
  • View reference in article

• 52

  LepetitHEddahibiSFadelEFrisdalEMunautCNoelAet al. Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J (2005) 25:834–42. doi: 10.1183/09031936.05.00072504

  • CrossRef
  • Google Scholar
  • View reference in article

• 53

  GolobMJTabimaDMWolfGDJohnstonJLForouzanOMulchroneAMet al. Pulmonary arterial strain- and remodeling-induced stiffening are differentiated in a chronic model of pulmonary hypertension. J Biomech (2017) 55:92–8. doi: 10.1016/j.jbiomech.2017.02.003

  • CrossRef
  • Google Scholar

• 54

  DemerLLTintutY. Vascular calcification: Pathobiology of a multifaceted disease. Circulation (2008) 117:2938–48. doi: 10.1161/CIRCULATIONAHA.107.743161

  • CrossRef
  • Google Scholar

• 55

  RuffenachGChabotSTanguayVFCourboulinABoucheratOPotusFet al. Role for runt-related transcription factor 2 in proliferative and calcified vascular lesions in pulmonary arterial hypertension. Am J Respir Crit Care Med (2016) 194:1273–85. doi: 10.1164/rccm.201512-2380OC

  • CrossRef
  • Google Scholar

• 56

  SunYByonCHYuanKChenJMaoXHeathJMet al. Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification. Circ Res (2012) 111:543–52. doi: 10.1161/CIRCRESAHA.112.267237

  • CrossRef
  • Google Scholar

• 57

  FriesenRMSchaferMIvyDDAbmanSHStenmarkKBrowneLPet al. Proximal pulmonary vascular stiffness as a prognostic factor in children with pulmonary arterial hypertension. Eur Heart J Cardiovasc Imaging (2019) 20:209–17. doi: 10.1093/ehjci/jey069

  • CrossRef
  • Google Scholar

• 58

  LiMTanYStenmarkKRTanW. High pulsatility flow induces acute endothelial inflammation through overpolarizing cells to activate NF-kappaB. Cardiovasc Eng Technol (2013) 4:26–38. doi: 10.1007/s13239-012-0115-5

  • CrossRef
  • Google Scholar

• 59

  SteppanJBarodkaVBerkowitzDENyhanD. Vascular stiffness and increased pulse pressure in the aging cardiovascular system. Cardiol Res Pract (2011) 2011:263585. doi: 10.4061/2011/263585

  • CrossRef
  • Google Scholar

• 60

  SteinerMKSyrkinaOLKolliputiNMarkEJHalesCAWaxmanAB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res (2009) 104:236–44. doi: 10.1161/CIRCRESAHA.108.182014

  • CrossRef
  • Google Scholar

• 61

  HuangWLiuHPanYYangHLinJZhangH. Mechanical stretching of the pulmonary vein mediates pulmonary hypertension due to left heart disease by regulating SAC/MAPK pathway and the expression of IL-6 and TNF-alpha. J Cardiothorac Surg (2021) 16:127. doi: 10.1186/s13019-021-01471-5

  • CrossRef
  • Google Scholar

• 62

  HurlimannDForsterANollGEnseleitFChenevardRDistlerOet al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation (2002) 106:2184–7. doi: 10.1161/01.CIR.0000037521.71373.44

  • CrossRef
  • Google Scholar

• 63

  ZhuYHuangYJiQFuSGuJTaiNet al. Interplay between extracellular matrix and neutrophils in diseases. J Immunol Res (2021) 2021:8243378. doi: 10.1155/2021/8243378

  • CrossRef
  • Google Scholar

• 64

  TenkorangMAAChaliseUDaseke IiMJKonfrstSRLindseyML. Understanding the mechanisms that determine extracellular matrix remodeling in the infarcted myocardium. Biochem Soc Trans (2019) 47:1679–87. doi: 10.1042/BST20190113

  • CrossRef
  • Google Scholar

• 65

  MaZMaoCJiaYFuYKongW. Extracellular matrix dynamics in vascular remodeling. Am J Physiol Cell Physiol (2020) 319:C481–99. doi: 10.1152/ajpcell.00147.2020

  • CrossRef
  • Google Scholar

• 66

  UdjusCCeroFTHalvorsenBBehmenDCarlsonCRBendiksenBAet al. Caspase-1 induces smooth muscle cell growth in hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol (2019) 316:L999–L1012. doi: 10.1152/ajplung.00322.2018

  • CrossRef
  • Google Scholar

• 67

  ParpaleixAAmsellemVHoussainiAAbidSBreauMMarcosEet al. Role of interleukin-1 receptor 1/MyD88 signalling in the development and progression of pulmonary hypertension. Eur Respir J (2016) 48:470–83. doi: 10.1183/13993003.01448-2015

  • CrossRef
  • Google Scholar

• 68

  TangCLuoYLiSHuangBXuSLiL. Characteristics of inflammation process in monocrotaline-induced pulmonary arterial hypertension in rats. BioMed Pharmacother (2021) 133:111081. doi: 10.1016/j.biopha.2020.111081

  • CrossRef
  • Google Scholar

• 69

  KoudstaalTvan HulstJACDasTNeysSFHMerkusDBergenIMet al. DNGR1-cre-mediated deletion of Tnfaip3/A20 in conventional dendritic cells induces pulmonary hypertension in mice. Am J Respir Cell Mol Biol (2020) 63:665–80. doi: 10.1165/rcmb.2019-0443OC

  • CrossRef
  • Google Scholar

• 70

  WangJTianXTPengZLiWQCaoYYLiYet al. HMGB1/TLR4 promotes hypoxic pulmonary hypertension via suppressing BMPR2 signaling. Vascul Pharmacol (2019) 117:35–44. doi: 10.1016/j.vph.2018.12.006

  • CrossRef
  • Google Scholar

• 71

  LiMRiddleSRFridMGEl KasmiKCMcKinseyTASokolRJet al. Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J Immunol (2011) 187:2711–22. doi: 10.4049/jimmunol.1100479

  • CrossRef
  • Google Scholar

• 72

  SmoldersVLodderKRodriguezCTura-CeideOBarberaJAJukemaJWet al. The inflammatory profile of CTEPH-derived endothelial cells is a possible driver of disease progression. Cells (2021) 10(4):737. doi: 10.3390/cells10040737

  • CrossRef
  • Google Scholar

• 73

  GaillardVCasellasDSeguin-DevauxCSchohnHDaucaMAtkinsonJet al. Pioglitazone improves aortic wall elasticity in a rat model of elastocalcinotic arteriosclerosis. Hypertension (2005) 46:372–9. doi: 10.1161/01.HYP.0000171472.24422.33

  • CrossRef
  • Google Scholar

• 74

  SantiagoJJDangerfieldALRattanSGBatheKLCunningtonRHRaizmanJEet al. Cardiac fibroblast to myofibroblast differentiation in vivo and in vitro: expression of focal adhesion components in neonatal and adult rat ventricular myofibroblasts. Dev Dyn (2010) 239:1573–84. doi: 10.1002/dvdy.22280

  • CrossRef
  • Google Scholar

• 75

  Sanchez-DuffhuesGGarcia de VinuesaAvan de PolVGeertsMEde VriesMRJansonSGet al. Inflammation induces endothelial-to-mesenchymal transition and promotes vascular calcification through downregulation of BMPR2. J Pathol (2019) 247:333–46. doi: 10.1002/path.5193

  • CrossRef
  • Google Scholar

• 76

  TomaszewskiMGrywalskaETomaszewskiABlaszczakPKurzynaMRolinskiJet al. Overexpression of PD-1 on peripheral blood lymphocytes in patients with idiopathic pulmonary arterial hypertension and its association with high viral loads of Epstein-Barr virus and poor clinical parameters. J Clin Med (2020) 9(6):1966. doi: 10.3390/jcm9061966

  • CrossRef
  • Google Scholar

• 77

  MajeedBTawinwungSEbersonLSSecombTWLarmonierNLarsonDF. Interleukin-2/Anti-Interleukin-2 immune complex expands regulatory T cells and reduces angiotensin II-induced aortic stiffening. Int J Hypertens (2014) 2014:126365. doi: 10.1155/2014/126365

  • CrossRef
  • Google Scholar

• 78

  ChaouatASavaleLChouaidCTuLSztrymfBCanuetMet al. Role for interleukin-6 in COPD-related pulmonary hypertension. Chest (2009) 136:678–87. doi: 10.1378/chest.08-2420

  • CrossRef
  • Google Scholar

• 79

  SweattAJHedlinHKBalasubramanianVHsiABlumLKRobinsonWHet al. Discovery of distinct immune phenotypes using machine learning in pulmonary arterial hypertension. Circ Res (2019) 124:904–19. doi: 10.1161/CIRCRESAHA.118.313911

  • CrossRef
  • Google Scholar

• 80

  KoudstaalTvan UdenDvan HulstJACHeukelsPBergenIMGeenenLWet al. Plasma markers in pulmonary hypertension subgroups correlate with patient survival. Respir Res (2021) 22:137. doi: 10.1186/s12931-021-01716-w

  • CrossRef
  • Google Scholar

• 81

  RanchouxBNadeauVBourgeoisAProvencherSTremblayEOmuraJet al. Metabolic syndrome exacerbates pulmonary hypertension due to left heart disease. Circ Res (2019) 125:449–66. doi: 10.1161/CIRCRESAHA.118.314555

  • CrossRef
  • Google Scholar

• 82

  Hashimoto-KataokaTHosenNSonobeTAritaYYasuiTMasakiTet al. Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci U.S.A. (2015) 112:E2677–2686. doi: 10.1073/pnas.1424774112

  • CrossRef
  • Google Scholar

• 83

  BatahSSAldaMARodrigues Lopes Roslindo FigueiraRCruvinelHRPerdona Rodrigues da SilvaLMachado-RugoloJet al. In situ evidence of collagen V and interleukin-6/Interleukin-17 activation in vascular remodeling of experimental pulmonary hypertension. Pathobiol (2020) 87:356–66. doi: 10.1159/000510048

  • CrossRef
  • Google Scholar

• 84

  SimpsonCEChenJYDamicoRLHassounPMMartinLJYangJet al. Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension. Eur Respir J (2020) 55(4):1901761. doi: 10.1183/13993003.01761-2019

  • CrossRef
  • Google Scholar

• 85

  HeHTaoYChenXQiuHZhuJZhangJet al. High levels of interleukin-6 and 8-iso-prostaglandin in the exhaled breath condensate and serum of patients with chronic obstructive pulmonary disease related pulmonary hypertension. Chin Med J (Engl) (2014) 127:1608–12.

  • Google Scholar

• 86

  KhanYMKirkhamPBarnesPJAdcockIM. Brd4 is essential for IL-1beta-induced inflammation in human airway epithelial cells. PloS One (2014) 9(4):e95051. doi: 10.1371/journal.pone.0095051

  • CrossRef
  • Google Scholar

• 87

  MelocheJPotusFVaillancourtMBourgeoisAJohnsonIDeschampsLet al. Bromodomain-containing protein 4: The epigenetic origin of pulmonary arterial hypertension. Circ Res (2015) 117:525–35. doi: 10.1161/CIRCRESAHA.115.307004

  • CrossRef
  • Google Scholar

• 88

  ManiatisKSiasosGOikonomouEVavuranakisMZaromytidouMMourouzisKet al. Osteoprotegerin and osteopontin serum levels are associated with vascular function and inflammation in coronary artery disease patients. Curr Vasc Pharmacol (2020) 18:523–30. doi: 10.2174/1570161117666191022095246

  • CrossRef
  • Google Scholar

• 89

  GokaslanSOzer GokaslanCDemirelECelikS. Role of aortic stiffness and inflammation in the etiology of young-onset hypertension. Turk J Med Sci (2019) 49(6):1748–53. doi: 10.3906/sag-1908-137

  • CrossRef
  • Google Scholar

• 90

  PeysterEChenJFeldmanHIGoASGuptaJMitraNet al. Inflammation and arterial stiffness in chronic kidney disease: Findings from the CRIC study. Am J Hypertens (2017) 30:400–8. doi: 10.1093/ajh/hpw164

  • CrossRef
  • Google Scholar

• 91

  QuarckRWynantsMVerbekenEMeynsBDelcroixM. Contribution of inflammation and impaired angiogenesis to the pathobiology of chronic thromboembolic pulmonary hypertension. Eur Respir J (2015) 46:431–43. doi: 10.1183/09031936.00009914

  • CrossRef
  • Google Scholar

• 92

  SikkaGMillerKLSteppanJPandeyDJungSMFraserCD3rdet al. Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age. . Exp Gerontol (2013) 48:128–35. doi: 10.1016/j.exger.2012.11.001

  • CrossRef
  • Google Scholar

• 93

  CalvierLLegchenkoEGrimmLSallmonHHatchAPlouffeBDet al. Galectin-3 and aldosterone as potential tandem biomarkers in pulmonary arterial hypertension. Heart (2016) 102:390–6. doi: 10.1136/heartjnl-2015-308365

  • CrossRef
  • Google Scholar

• 94

  LarsenKOYndestadASjaastadILobergEMGoverudILHalvorsenBet al. Lack of CCR7 induces pulmonary hypertension involving perivascular leukocyte infiltration and inflammation. Am J Physiol Lung Cell Mol Physiol (2011) 301:L50–59. doi: 10.1152/ajplung.00048.2010

  • CrossRef
  • Google Scholar

• 95

  WangWYanHZhuWCuiYChenJWangXet al. Impairment of monocyte-derived dendritic cells in idiopathic pulmonary arterial hypertension. J Clin Immunol (2009) 29:705–13. doi: 10.1007/s10875-009-9322-8

  • CrossRef
  • Google Scholar

• 96

  YongKDograGBoudvilleNChanDAdamsLChingHet al. Interleukin-12 is associated with arterial stiffness in healthy individuals. Am J Hypertens (2013) 26:159–62. doi: 10.1093/ajh/hps032

  • CrossRef
  • Google Scholar

• 97

  ZhuRXieXWangNChenLHongY. The T helper type 17/regulatory T cell imbalance was associated with ras-GTPase overexpression in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease. Immunology (2019) 157(4):304–11. doi: 10.1111/imm.13084

  • CrossRef
  • Google Scholar

• 98

  HuangLHZinselmeyerBHChangCHSaundersBTElvingtonABabaOet al. Interleukin-17 drives interstitial entrapment of tissue lipoproteins in experimental psoriasis. Cell Metab (2019) 29:475–487 e477. doi: 10.1016/j.cmet.2018.10.006

  • CrossRef
  • Google Scholar

• 99

  YangMDengCWuDZhongZLvXHuangZet al. The role of mononuclear cell tissue factor and inflammatory cytokines in patients with chronic thromboembolic pulmonary hypertension. J Thromb Thrombol (2016) 42:38–45. doi: 10.1007/s11239-015-1323-2

  • CrossRef
  • Google Scholar

• 100

  SalebyJBouzinaHLundgrenJRadegranG. Angiogenic and inflammatory biomarkers in the differentiation of pulmonary hypertension. Scand Cardiovasc J (2017) 51:261–70. doi: 10.1080/14017431.2017.1359419

  • CrossRef
  • Google Scholar

• 101

  KylhammarDHesselstrandRNielsenSScheeleCRadegranG. Angiogenic and inflammatory biomarkers for screening and follow-up in patients with pulmonary arterial hypertension. Scand J Rheumatol (2018) 47:319–24. doi: 10.1080/03009742.2017.1378714

  • CrossRef
  • Google Scholar

• 102

  NaitoASakaoSTeradaJIwasawaSJujo SanadaTSudaRet al. Nocturnal hypoxemia and high circulating TNF-alpha levels in chronic thromboembolic pulmonary hypertension. Intern Med (2020) 59:1819–26. doi: 10.2169/internalmedicine.4458-20

  • CrossRef
  • Google Scholar

• 103

  BaiPLyuLYuTZuoCFuJHeYet al. Macrophage-derived legumain promotes pulmonary hypertension by activating the MMP (Matrix metalloproteinase)-2/TGF (Transforming growth factor)-beta1 signaling. Arterioscler Thromb Vasc Biol (2019) 39(4):e130–45. doi: 10.1161/ATVBAHA.118.312254

  • CrossRef
  • Google Scholar

• 104

  TintutYPatelJParhamiFDemerLL. Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation (2000) 102:2636–42. doi: 10.1161/01.CIR.102.21.2636

  • CrossRef
  • Google Scholar

• 105

  PinaTCorralesALopez-MejiasRArmestoSGonzalez-LopezMAGomez-AceboIet al. Anti-tumor necrosis factor-alpha therapy improves endothelial function and arterial stiffness in patients with moderate to severe psoriasis: A 6-month prospective study. J Dermatol (2016) 43:1267–72. doi: 10.1111/1346-8138.13398

  • CrossRef
  • Google Scholar

• 106

  MoreauKLDeaneKDMeditzALKohrtWM. Tumor necrosis factor-alpha inhibition improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women. Atherosclerosis (2013) 230:390–6. doi: 10.1016/j.atherosclerosis.2013.07.057

  • CrossRef
  • Google Scholar

• 107

  AngelKProvanSAGulsethHLMowinckelPKvienTKAtarD. Tumor necrosis factor-alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: a controlled study. Hypertension (2010) 55:333–8. doi: 10.1161/HYPERTENSIONAHA.109.143982

  • CrossRef
  • Google Scholar

• 108

  KumarRMickaelCChabonJGebreabLRutebemberwaAGarciaARet al. The causal role of IL-4 and IL-13 in schistosoma mansoni pulmonary hypertension. Am J Respir Crit Care Med (2015) 192:998–1008. doi: 10.1164/rccm.201410-1820OC

  • CrossRef
  • Google Scholar

• 109

  LiSMaXXieJYanXSunW. MicroRNA-206, IL-4, IL-13, and INF-gamma levels in lung tissue and plasma are increased by the stimulation of particulate matter with a diameter of </=2.5mum, and are associated with the poor prognosis of asthma induced pulmonary arterial hypertension patients. Clin Exp Hypertens (2021) 43:181–8. doi: 10.1080/10641963.2020.1836192

  • CrossRef
  • Google Scholar

• 110

  CeroFTHillestadVSjaastadIYndestadAAukrustPRanheimTet al. Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol (2015) 309:L378–387. doi: 10.1152/ajplung.00342.2014

  • CrossRef
  • Google Scholar

• 111

  ShaoDPerrosFCaramoriGMengCDormullerPChouPCet al. Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension. Biochem Biophys Res Commun (2014) 451:8–14. doi: 10.1016/j.bbrc.2014.06.111

  • CrossRef
  • Google Scholar

• 112

  CarlomagnoGMessalliGMelilloRMStanziolaAAViscianoCMercurioVet al. Serum soluble ST2 and interleukin-33 levels in patients with pulmonary arterial hypertension. Int J Cardiol (2013) 168:1545–7. doi: 10.1016/j.ijcard.2012.12.031

  • CrossRef
  • Google Scholar

• 113

  LiuJWangWWangLChenSTianBHuangKet al. IL-33 initiates vascular remodelling in hypoxic pulmonary hypertension by up-regulating HIF-1alpha and VEGF expression in vascular endothelial cells. EBioMedicine (2018) 33:196–210. doi: 10.1016/j.ebiom.2018.06.003

  • CrossRef
  • Google Scholar

• 114

  AmsellemVAbidSPoupelLParpaleixARoderoMGary-BoboGet al. Roles for the CX3CL1/CX3CR1 and CCL2/CCR2 chemokine systems in hypoxic pulmonary hypertension. Am J Respir Cell Mol Biol (2017) 56:597–608. doi: 10.1165/rcmb.2016-0201OC

  • CrossRef
  • Google Scholar

• 115

  AbidSMarcosEParpaleixAAmsellemVBreauMHoussainiAet al. CCR2/CCR5-mediated macrophage-smooth muscle cell crosstalk in pulmonary hypertension. Eur Respir J (2019) 54(4):1802308. doi: 10.1183/13993003.02308-2018

  • CrossRef
  • Google Scholar

• 116

  BakouboulaBMorelOFaureAZobairiFJeselLTrinhAet al. Procoagulant membrane microparticles correlate with the severity of pulmonary arterial hypertension. Am J Respir Crit Care Med (2008) 177:536–43. doi: 10.1164/rccm.200706-840OC

  • CrossRef
  • Google Scholar

• 117

  ChangFCChiangWCTsaiMHChouYHPanSYChangYTet al. Angiopoietin-2-induced arterial stiffness in CKD. J Am Soc Nephrol (2014) 25:1198–209. doi: 10.1681/ASN.2013050542

  • CrossRef
  • Google Scholar

• 118

  QiDWeiMJiaoSSongYWangXXieGet al. Hypoxia inducible factor 1alpha in vascular smooth muscle cells promotes angiotensin II-induced vascular remodeling via activation of CCL7-mediated macrophage recruitment. Cell Death Dis (2019) 10:544. doi: 10.1038/s41419-019-1757-0

  • CrossRef
  • Google Scholar

• 119

  NieXTanJDaiYLiuYZouJSunJet al. CCL5 deficiency rescues pulmonary vascular dysfunction, and reverses pulmonary hypertension via caveolin-1-dependent BMPR2 activation. J Mol Cell Cardiol (2018) 116:41–56. doi: 10.1016/j.yjmcc.2018.01.016

  • CrossRef
  • Google Scholar

• 120

  AmsellemVLipskaiaLAbidSPoupelLHoussainiAQuarckRet al. CCR5 as a treatment target in pulmonary arterial hypertension. Circulation (2014) 130:880–91. doi: 10.1161/CIRCULATIONAHA.114.010757

  • CrossRef
  • Google Scholar

• 121

  ZengYLiNZhengZChenRPengMLiuWet al. Screening of hub genes associated with pulmonary arterial hypertension by integrated bioinformatic analysis. BioMed Res Int (2021) 2021:6626094. doi: 10.1155/2021/6626094

  • CrossRef
  • Google Scholar

• 122

  DorfmullerPZarkaVDurand-GasselinIMontiGBalabanianKGarciaGet al. Chemokine RANTES in severe pulmonary arterial hypertension. Am J Respir Crit Care Med (2002) 165:534–9. doi: 10.1164/ajrccm.165.4.2012112

  • CrossRef
  • Google Scholar

• 123

  XuJLiXZhouSWangRWuMTanCet al. Inhibition of CXCR4 ameliorates hypoxia-induced pulmonary arterial hypertension in rats. Am J Transl Res (2021) 13:1458–70.

  • Google Scholar

• 124

  BordenaveJThuilletRTuLPhanCCumontAMarsolCet al. Neutralization of CXCL12 attenuates established pulmonary hypertension in rats. Cardiovasc Res (2020) 116:686–97. doi: 10.1093/cvr/cvz153

  • CrossRef
  • Google Scholar

• 125

  OlssonKMOlleSFugeJWelteTHoeperMMLerchCet al. CXCL13 in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Respir Res (2016) 17:21. doi: 10.1186/s12931-016-0336-5

  • CrossRef
  • Google Scholar

• 126

  ZhangYLinPHongCJiangQXingYTangXet al. Serum cytokine profiles in patients with chronic obstructive pulmonary disease associated pulmonary hypertension identified using protein array. Cytokine (2018) 111:342–9. doi: 10.1016/j.cyto.2018.09.005

  • CrossRef
  • Google Scholar

• 127

  DelaneyCDavizon-CastilloPAllawziAPoseyJGandjevaANeevesKet al. Platelet activation contributes to hypoxia-induced inflammation. Am J Physiol Lung Cell Mol Physiol (2021) 320:L413–21. doi: 10.1152/ajplung.00519.2020

  • CrossRef
  • Google Scholar

• 128

  ZawiaAArnoldNDWestLPickworthJATurtonHIremongerJet al. Altered macrophage polarization induces experimental pulmonary hypertension and is observed in patients with pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol (2021) 41(1):430–45. doi: 10.1161/ATVBAHA.120.314639

  • CrossRef
  • Google Scholar

• 129

  WangLZhangXCaoYMaQMaoXXuJet al. Mice with a specific deficiency of Pfkfb3 in myeloid cells are protected from hypoxia-induced pulmonary hypertension. Br J Pharmacol (2021) 178:1055–72. doi: 10.1111/bph.15339

  • CrossRef
  • Google Scholar

• 130

  XiXZhangJWangJChenYZhangWZhangXet al. SGK1 mediates hypoxic pulmonary hypertension through promoting macrophage infiltration and activation. Anal Cell Pathol (Amst) (2019) 2019:3013765. doi: 10.1155/2019/3013765

  • CrossRef
  • Google Scholar

• 131

  BochenekMLRosinusNSLankeitMHobohmLBremmerFSchutzEet al. From thrombosis to fibrosis in chronic thromboembolic pulmonary hypertension. Thromb Haemost (2017) 117:769–83. doi: 10.1160/TH16-10-0790

  • CrossRef
  • Google Scholar

• 132

  MiaoRDongXGongJLiYGuoXWangJet al. Cell landscape atlas for patients with chronic thromboembolic pulmonary hypertension after pulmonary endarterectomy constructed using single-cell RNA sequencing. Aging (Albany NY) (2021) 13:16485–99. doi: 10.18632/aging.203168

  • CrossRef
  • Google Scholar

• 133

  PriceLCCaramoriGPerrosFMengCGambaryanNDorfmullerPet al. Nuclear factor kappa-b is activated in the pulmonary vessels of patients with end-stage idiopathic pulmonary arterial hypertension. PloS One (2013) 8(10):e75415. doi: 10.1371/journal.pone.0075415

  • CrossRef
  • Google Scholar

• 134

  MasakiTOkazawaMAsanoRInagakiTIshibashiTYamagishiAet al. Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci U.S.A. (2021) 118(11):e2023899118. doi: 10.1073/pnas.2023899118

  • CrossRef
  • Google Scholar

• 135

  LariviereRGauthier-BastienAUngRVSt-HilaireJMac-WayFRichardDEet al. Endothelin type a receptor blockade reduces vascular calcification and inflammation in rats with chronic kidney disease. J Hypertens (2017) 35:376–84. doi: 10.1097/HJH.0000000000001161

  • CrossRef
  • Google Scholar

• 136

  ChenJYWuYPLiCYJhengHFKaoLZYangCCet al. PPARgamma activation improves the microenvironment of perivascular adipose tissue and attenuates aortic stiffening in obesity. J BioMed Sci (2021) 28:22. doi: 10.1186/s12929-021-00720-y

  • CrossRef
  • Google Scholar

• 137

  SharmaNDevRBelenchiaAMAroorARWhaley-ConnellAPulakatLet al. Deficiency of IL12p40 (Interleukin 12 p40) promotes ang II (Angiotensin II)-induced abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol (2019) 39:212–23. doi: 10.1161/ATVBAHA.118.311969

  • CrossRef
  • Google Scholar

• 138

  TamosiunieneRManouvakhovaOMesangePSaitoTQianJSanyalMet al. Dominant role for regulatory T cells in protecting females against pulmonary hypertension. Circ Res (2018) 122:1689–702. doi: 10.1161/CIRCRESAHA.117.312058

  • CrossRef
  • Google Scholar

• 139

  ChuYXiangliXXiaoW. Regulatory T cells protect against hypoxia-induced pulmonary arterial hypertension in mice. Mol Med Rep (2015) 11:3181–7. doi: 10.3892/mmr.2014.3106

  • CrossRef
  • Google Scholar

• 140

  OrmistonMLChangCLongLLSoonEJonesDMachadoRet al. Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension. Circulation (2012) 126:1099–109. doi: 10.1161/CIRCULATIONAHA.112.110619

  • CrossRef
  • Google Scholar

• 141

  MaoMZhangMGeAGeXGuRZhangCet al. Granzyme b deficiency promotes osteoblastic differentiation and calcification of vascular smooth muscle cells in hypoxic pulmonary hypertension. Cell Death Dis (2018) 9:221. doi: 10.1038/s41419-018-0315-5

  • CrossRef
  • Google Scholar

• 142

  MastonLDJonesDTGiermakowskaWHowardTACannonJLWangWet al. Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol (2017) 312:L609–24. doi: 10.1152/ajplung.00531.2016

  • CrossRef
  • Google Scholar

• 143

  KellyCMwandumbaHCHeydermanRSJamboKKamng'onaRChammudziMet al. HIV-Related arterial stiffness in Malawian adults is associated with the proportion of PD-1-Expressing CD8+ T cells and reverses with antiretroviral therapy. J Infect Dis (2019) 219:1948–58. doi: 10.1093/infdis/jiz015

  • CrossRef
  • Google Scholar

• 144

  FlorentinJZhaoJTaiYYVasamsettiSBO'NeilSPKumarRet al. Interleukin-6 mediates neutrophil mobilization from bone marrow in pulmonary hypertension. Cell Mol Immunol (2021) 18:374–84. doi: 10.1038/s41423-020-00608-1

  • CrossRef
  • Google Scholar

• 145

  StrokaKMLevitanIAranda-EspinozaH. OxLDL and substrate stiffness promote neutrophil transmigration by enhanced endothelial cell contractility and ICAM-1. J Biomech (2012) 45:1828–34. doi: 10.1016/j.jbiomech.2012.04.011

  • CrossRef
  • Google Scholar

• 146

  HoffmannJYinJKukuckaMYinNSaarikkoISterner-KockAet al. Mast cells promote lung vascular remodelling in pulmonary hypertension. Eur Respir J (2011) 37:1400–10. doi: 10.1183/09031936.00043310

  • CrossRef
  • Google Scholar

• 147

  BarteldsBvan LoonRLEMohauptSWijnbergHDickinsonMGBoersmaBet al. Mast cell inhibition improves pulmonary vascular remodeling in pulmonary hypertension. Chest (2012) 141:651–60. doi: 10.1378/chest.11-0663

  • CrossRef
  • Google Scholar

• 148

  DahalBKKosanovicDKaulenCCornitescuTSavaiRHoffmannJet al. Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats. Respir Res (2011) 12:60. doi: 10.1186/1465-9921-12-60

  • CrossRef
  • Google Scholar

• 149

  FarhaSSharpJAsosinghKParkMComhairSATangWHet al. Mast cell number, phenotype, and function in human pulmonary arterial hypertension. Pulm Circ (2012) 2:220–8. doi: 10.4103/2045-8932.97609

  • CrossRef
  • Google Scholar

• 150

  WengMBaronDMBlochKDLusterADLeeJJMedoffBD. Eosinophils are necessary for pulmonary arterial remodeling in a mouse model of eosinophilic inflammation-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol (2011) 301:L927–936. doi: 10.1152/ajplung.00049.2011

  • CrossRef
  • Google Scholar

• 151

  SunLNingCLiuJYaoTZhangLZhaoLet al. The association between cumulative c-reactive protein and brachial-ankle pulse wave velocity. Aging Clin Exp Res (2020) 32:789–96. doi: 10.1007/s40520-019-01274-8

  • CrossRef
  • Google Scholar

• 152

  ScottHAQuachBYangXArdekaniSCabreraAPWilsonRet al. Matrix stiffness exerts biphasic control over monocyte-endothelial adhesion via rho-mediated ICAM-1 clustering. Integr Biol (Camb) (2016) 8:869–78. doi: 10.1039/C6IB00084C

  • CrossRef
  • Google Scholar

• 153

  DengHSongZXuHDengXZhangQChenHet al. MicroRNA-1185 promotes arterial stiffness though modulating VCAM-1 and e-selectin expression. Cell Physiol Biochem (2017) 41:2183–93. doi: 10.1159/000475576

  • CrossRef
  • Google Scholar

• 154

  SunWChanSY. Pulmonary arterial stiffness: An early and pervasive driver of pulmonary arterial hypertension. Front Med (Lausanne) (2018) 5:204. doi: 10.3389/fmed.2018.00204

  • CrossRef
  • Google Scholar

• 155

  WangZLakesRSEickhoffJCCheslerNC. Effects of collagen deposition on passive and active mechanical properties of large pulmonary arteries in hypoxic pulmonary hypertension. Biomech Model Mechanobiol (2013) 12:1115–25. doi: 10.1007/s10237-012-0467-7

  • CrossRef
  • Google Scholar

• 156

  FranzMGrunKBetgeSRohmINdongson-DongmoBBauerRet al. Lung tissue remodelling in MCT-induced pulmonary hypertension: A proposal for a novel scoring system and changes in extracellular matrix and fibrosis associated gene expression. Oncotarget (2016) 7:81241–54. doi: 10.18632/oncotarget.13220

  • CrossRef
  • Google Scholar

• 157

  ThenappanTPrinsKWPritzkerMRScandurraJVolmersKWeirEK. The critical role of pulmonary arterial compliance in pulmonary hypertension. Ann Am Thorac Soc (2016) 13:276–84. doi: 10.1513/AnnalsATS.201509-599FR

  • CrossRef
  • Google Scholar

• 158

  MorenoJEscobedoDCalhounCLe SauxCJHanHC. Arterial wall stiffening in caveolin-1 deficiency-induced pulmonary artery hypertension in mice. Exp Mech (2021) 6:217–28. doi: 10.1007/s11340-020-00666-6

  • CrossRef
  • Google Scholar

• 159

  MierkeJChristophMAugsteinAPflueckeCJellinghausSWoitekFet al. Influence of caveolin-1 and endothelial nitric oxide synthase on adventitial inflammation in aortic transplants. Kardiol Pol (2020) 78:124–30. doi: 10.33963/KP.15079

  • CrossRef
  • Google Scholar

• 160

  BloodworthNCClarkCRWestJDSniderJCGaskillCShaySet al. Bone marrow-derived proangiogenic cells mediate pulmonary arteriole stiffening via serotonin 2B receptor dependent mechanism. Circ Res (2018) 123:e51–64. doi: 10.1161/CIRCRESAHA.118.313397

  • CrossRef
  • Google Scholar

• 161

  Quintero-VillegasAValdes-FerrerSI. Role of 5-HT7 receptors in the immune system in health and disease. Mol Med (2019) 26:2. doi: 10.1186/s10020-019-0126-x

  • CrossRef
  • Google Scholar

• 162

  SchaferMIvyDDNguyenKBoncellaKFrankBSMorganGJet al. Metalloproteinases and their inhibitors are associated with pulmonary arterial stiffness and ventricular function in pediatric pulmonary hypertension. Am J Physiol Heart Circ Physiol (2021) 321:H242–52. doi: 10.1152/ajpheart.00750.2020

  • CrossRef
  • Google Scholar

• 163

  LammersSScottDHunterKTanWShandasRStenmarkKR. Mechanics and function of the pulmonary vasculature: implications for pulmonary vascular disease and right ventricular function. Compr Physiol (2012) 2:295–319. doi: 10.1002/cphy.c100070

  • CrossRef
  • Google Scholar

• 164

  ProtogerouADZampeliEFragiadakiKStamatelopoulosKPapamichaelCSfikakisPP. A pilot study of endothelial dysfunction and aortic stiffness after interleukin-6 receptor inhibition in rheumatoid arthritis. Atherosclerosis (2011) 219:734–6. doi: 10.1016/j.atherosclerosis.2011.09.015

  • CrossRef
  • Google Scholar

• 165

  TuttolomondoAPecoraroRDi RaimondoDDi SciaccaRCaninoBArnaoVet al. Immune-inflammatory markers and arterial stiffness indexes in subjects with acute ischemic stroke with and without metabolic syndrome. Diabetol Metab Syndr (2014) 6:28. doi: 10.1186/1758-5996-6-28

  • CrossRef
  • Google Scholar

• 166

  HurstLADunmoreBJLongLCrosbyAAl-LamkiRDeightonJet al. TNFalpha drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nat Commun (2017) 8:14079. doi: 10.1038/ncomms14079

  • CrossRef
  • Google Scholar

• 167

  VlachopoulosCGravosAGeorgiopoulosGTerentes-PrintziosDIoakeimidisNVassilopoulosDet al. The effect of TNF-a antagonists on aortic stiffness and wave reflections: a meta-analysis. Clin Rheumatol (2018) 37:515–26. doi: 10.1007/s10067-017-3657-y

  • CrossRef
  • Google Scholar

• 168

  FrangogiannisNG. The extracellular matrix in ischemic and nonischemic heart failure. Circ Res (2019) 125:117–46. doi: 10.1161/CIRCRESAHA.119.311148

  • CrossRef
  • Google Scholar

• 169

  ZhangJTangLDaiFQiYYangLLiuZet al. ROCK inhibitors alleviate myofibroblast transdifferentiation and vascular remodeling via decreasing TGFbeta1-mediated RhoGDI expression. Gen Physiol Biophys (2019) 38:271–80. doi: 10.4149/gpb_2019017

  • CrossRef
  • Google Scholar

• 170

  BaumJDuffyHS. Fibroblasts and myofibroblasts: what are we talking about? J Cardiovasc Pharmacol (2011) 57:376–9. doi: 10.1097/FJC.0b013e3182116e39

  • CrossRef
  • Google Scholar

• 171

  AnwarALiMFridMGKumarBGerasimovskayaEVRiddleSRet al. Osteopontin is an endogenous modulator of the constitutively activated phenotype of pulmonary adventitial fibroblasts in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol (2012) 303:L1–L11. doi: 10.1152/ajplung.00050.2012

  • CrossRef
  • Google Scholar

• 172

  BarmanSAChenFSuYDimitropoulouCWangYCatravasJDet al. NADPH oxidase 4 is expressed in pulmonary artery adventitia and contributes to hypertensive vascular remodeling. Arterioscler Thromb Vasc Biol (2014) 34:1704–15. doi: 10.1161/ATVBAHA.114.303848

  • CrossRef
  • Google Scholar

• 173

  ChazovaILoydJEZhdanovVSNewmanJHBelenkovYMeyrickB. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol (1995) 146:389–97.

  • Google Scholar

• 174

  ChanECPeshavariyaHMLiuGSJiangFLimSYDustingGJ. Nox4 modulates collagen production stimulated by transforming growth factor beta1 in vivo and in vitro. Biochem Biophys Res Commun (2013) 430:918–25. doi: 10.1016/j.bbrc.2012.11.138

  • CrossRef
  • Google Scholar

• 175

  LinYCSungYKJiangXPeters-GoldenMNicollsMR. Simultaneously targeting myofibroblast contractility and extracellular matrix cross-linking as a therapeutic concept in airway fibrosis. Am J Transplant (2017) 17:1229–41. doi: 10.1111/ajt.14103

  • CrossRef
  • Google Scholar

• 176

  NaveAHMizikovaINiessGSteenbockHReichenbergerFTalaveraMLet al. Lysyl oxidases play a causal role in vascular remodeling in clinical and experimental pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol (2014) 34:1446–58. doi: 10.1161/ATVBAHA.114.303534

  • CrossRef
  • Google Scholar

• 177

  RaazUSchellingerINChernogubovaEWarneckeCKayamaYPenovKet al. Transcription factor Runx2 promotes aortic fibrosis and stiffness in type 2 diabetes mellitus. Circ Res (2015) 117:513–24. doi: 10.1161/CIRCRESAHA.115.306341

  • CrossRef
  • Google Scholar

• 178

  BendeckMPIrvinCReidyMA. Inhibition of matrix metalloproteinase activity inhibits smooth muscle cell migration but not neointimal thickening after arterial injury. Circ Res (1996) 78:38–43. doi: 10.1161/01.RES.78.1.38

  • CrossRef
  • Google Scholar

• 179

  MutganACJandlKKwapiszewskaG. Endothelial basement membrane components and their products, matrikines: Active drivers of pulmonary hypertension? Cells (2020) 9(9):2029. doi: 10.3390/cells9092029

  • CrossRef
  • Google Scholar

• 180

  BizbizLBonithon-KoppCDucimetierePBerrCAlperovitchARobertL. Relation of serum elastase activity to ultrasonographically assessed carotid artery wall lesions and cardiovascular risk factors. EVA study Atheroscl (1996) 120:47–55. doi: 10.1016/0021-9150(95)05676-9

  • CrossRef
  • Google Scholar

• 181

  YasminMcEnieryCMWallaceSDakhamZPulsalkarPMaki-PetajaKet al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol (2005) 25:372. doi: 10.1161/01.ATV.0000151373.33830.41

  • CrossRef
  • Google Scholar

• 182

  Diaz-CanestroCPuspitasariYMLiberaleLGuzikTJFlammerAJBonettiNRet al. MMP-2 knockdown blunts age-dependent carotid stiffness by decreasing elastin degradation and augmenting eNOS activation. Cardiovasc Res (2021) 118 (10):2385–96. doi: 10.1093/eurheartj/ehab724.3378

  • CrossRef
  • Google Scholar

• 183

  XiongWMacTaggartJKnispelRWorthJPersidskyYBaxterBT. Blocking TNF-alpha attenuates aneurysm formation in a murine model. J Immunol (2009) 183:2741–6. doi: 10.4049/jimmunol.0803164

  • CrossRef
  • Google Scholar

• 184

  LeopoldJA. Vascular calcification: Mechanisms of vascular smooth muscle cell calcification. Trends Cardiovasc Med (2015) 25:267–74. doi: 10.1016/j.tcm.2014.10.021

  • CrossRef
  • Google Scholar

• 185

  HaydenMRTyagiSCKolbLSowersJRKhannaR. Vascular ossification-calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis-calcific uremic arteriolopathy: The emerging role of sodium thiosulfate. Cardiovasc Diabetol (2005) 4:4. doi: 10.1186/1475-2840-4-4

  • CrossRef
  • Google Scholar

• 186

  WengJJSuY. Nuclear matrix-targeting of the osteogenic factor Runx2 is essential for its recognition and activation of the alkaline phosphatase gene. Biochim Biophys Acta (2013) 1830:2839–52. doi: 10.1016/j.bbagen.2012.12.021

  • CrossRef
  • Google Scholar

• 187

  CuiRRLiSJLiuLJYiLLiangQHZhuXet al. MicroRNA-204 regulates vascular smooth muscle cell calcification in vitro and in vivo. Cardiovasc Res (2012) 96:320–9. doi: 10.1093/cvr/cvs258

  • CrossRef
  • Google Scholar

• 188

  ZhangJZhengBZhouPPZhangRNHeMYangZet al. Vascular calcification is coupled with phenotypic conversion of vascular smooth muscle cells through Klf5-mediated transactivation of the Runx2 promoter. Biosci Rep (2014) 34:e00148. doi: 10.1042/BSR20140103

  • CrossRef
  • Google Scholar

• 189

  GutierrezFRMoranCJLudbrookPAMcKnightRCWeldonCS. Pulmonary arterial calcification with reversible pulmonary hypertension. AJR Am J Roentgenol (1980) 135:177–8. doi: 10.2214/ajr.135.1.177

  • CrossRef
  • Google Scholar

• 190

  AkmalMBarndtRRAnsariANMohlerJGMassrySG. Excess PTH in CRF induces pulmonary calcification, pulmonary hypertension and right ventricular hypertrophy. Kidney Int (1995) 47:158–63. doi: 10.1038/ki.1995.18

  • CrossRef
  • Google Scholar

• 191

  OhyamaYTsuchiyaHKurosawaKNakanoAAraiMNobusawaSet al. Pulmonary hypertension with extensive calcification in small pulmonary vessels and alveolar capillary wall in a chronic hemodialysis patient. J Cardiol cases (2013) 8:e13–6. doi: 10.1016/j.jccase.2013.02.015

  • CrossRef
  • Google Scholar

• 192

  Aluja JaramilloFGutierrezFRDiaz TelliFGYevenes AravenaSJavidan-NejadCBhallaS. Approach to pulmonary hypertension: From CT to clinical diagnosis. Radiographics (2018) 38:357–73. doi: 10.1148/rg.2018170046

  • CrossRef
  • Google Scholar

• 193

  TanguayVFBabinCGiardettiGSohier-PoirierCMenard-CholetteVRanchouxBet al. Enhanced pulmonary artery radiodensity in pulmonary arterial hypertension: A sign of early calcification? Am J Respir Crit Care Med (2019) 199:799–802. doi: 10.1164/rccm.201806-1027LE

  • CrossRef
  • Google Scholar

• 194

  PhilpT. Pulmonary artery calcification. Scott Med J (1972) 17:104–7. doi: 10.1177/003693307201700305

  • CrossRef
  • Google Scholar

• 195

  MaCGuRWangXHeSBaiJZhangLet al. circRNA CDR1as promotes pulmonary artery smooth muscle cell calcification by upregulating CAMK2D and CNN3 via sponging miR-7-5p. Mol Ther Nucleic Acids (2020) 22:530–41. doi: 10.1016/j.omtn.2020.09.018

  • CrossRef
  • Google Scholar

• 196

  ParhamiFBasseriBHwangJTintutYDemerLL. High-density lipoprotein regulates calcification of vascular cells. Circ Res (2002) 91:570–6. doi: 10.1161/01.RES.0000036607.05037.DA

  • CrossRef
  • Google Scholar

• 197

  ParadiseCRGalvanMLKubrovaEBowdenSLiuECarstensMFet al. The epigenetic reader Brd4 is required for osteoblast differentiation. J Cell Physiol (2020) 235:5293–304. doi: 10.1002/jcp.29415

  • CrossRef
  • Google Scholar

• 198

  SancisiVManzottiGGugnoniMRossiTGandolfiGGobbiGet al. RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN. Nucleic Acids Res (2017) 45:11249–67. doi: 10.1093/nar/gkx802

  • CrossRef
  • Google Scholar

• 199

  MelocheJLampronMCNadeauVMaltaisMPotusFLambertCet al. Implication of inflammation and epigenetic readers in coronary artery remodeling in patients with pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol (2017) 37:1513–23. doi: 10.1161/ATVBAHA.117.309156

  • CrossRef
  • Google Scholar

• 200

  Van der FeenDEKurakulaKTremblayEBoucheratOBossersGPLSzulcekRet al. Multicenter preclinical validation of BET inhibition for the treatment of pulmonary arterial hypertension. Am J Respir Crit Care Med (2019) 200:910–20. doi: 10.1164/rccm.201812-2275OC

  • CrossRef
  • Google Scholar

• 201

  WatsonKEParhamiFShinVDemerLL. Fibronectin and collagen I matrixes promote calcification of vascular cells in vitro, whereas collagen IV matrix is inhibitory. Arterioscler Thromb Vasc Biol (1998) 18:1964–71. doi: 10.1161/01.ATV.18.12.1964

  • CrossRef
  • Google Scholar

• 202

  KrohnJBHutchesonJDMartinez-MartinezEIrvinWSBoutenCVBertazzoSet al. Discoidin domain receptor-1 regulates calcific extracellular vesicle release in vascular smooth muscle cell fibrocalcific response via transforming growth factor-beta signaling. Arterioscler Thromb Vasc Biol (2016) 36:525–33. doi: 10.1161/ATVBAHA.115.307009

  • CrossRef
  • Google Scholar

• 203

  HodrogeATrecherelECornuMDarwicheWMansourAAit-MohandKet al. Oligogalacturonic acid inhibits vascular calcification by two mechanisms: Inhibition of vascular smooth muscle cell osteogenic conversion and interaction with collagen. Arterioscler Thromb Vasc Biol (2017) 37:1391–401. doi: 10.1161/ATVBAHA.117.309513

  • CrossRef
  • Google Scholar

• 204

  Piera-VelazquezSJimenezSA. Endothelial to mesenchymal transition: Role in physiology and in the pathogenesis of human diseases. Physiol Rev (2019) 99:1281–324. doi: 10.1152/physrev.00021.2018

  • CrossRef
  • Google Scholar

• 205

  GoodRBGilbaneAJTrinderSLDentonCPCoghlanGAbrahamDJet al. Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension. Am J Pathol (2015) 185:1850–8. doi: 10.1016/j.ajpath.2015.03.019

  • CrossRef
  • Google Scholar

• 206

  LiLKimIKChiassonVChatterjeePGuptaS. NF-kappaB mediated miR-130a modulation in lung microvascular cell remodeling: Implication in pulmonary hypertension. Exp Cell Res (2017) 359:235–42. doi: 10.1016/j.yexcr.2017.07.024

  • CrossRef
  • Google Scholar

• 207

  SuzukiTCarrierEJTalatiMHRathinasabapathyAChenXNishimuraRet al. Isolation and characterization of endothelial-to-mesenchymal transition cells in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol (2018) 314:L118–26. doi: 10.1152/ajplung.00296.2017

  • CrossRef
  • Google Scholar

• 208

  QiaoLNishimuraTShiLSessionsDThrasherATrudellJRet al. Endothelial fate mapping in mice with pulmonary hypertension. Circulation (2014) 129:692–703. doi: 10.1161/CIRCULATIONAHA.113.003734

  • CrossRef
  • Google Scholar

• 209

  CrnkovicSMarshLMEl AghaEVoswinckelRGhanimBKlepetkoWet al. Resident cell lineages are preserved in pulmonary vascular remodeling. J Pathol (2018) 244:485–98. doi: 10.1002/path.5044

  • CrossRef
  • Google Scholar

• 210

  DanQShiYRabaniRVenugopalSXiaoJAnwerSet al. Claudin-2 suppresses GEF-H1, RHOA, and MRTF, thereby impacting proliferation and profibrotic phenotype of tubular cells. J Biol Chem (2019) 294:15446–65. doi: 10.1074/jbc.RA118.006484

  • CrossRef
  • Google Scholar

• 211

  RanchouxBAntignyFRucker-MartinCHautefortAPechouxCBogaardHJet al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation (2015) 131:1006–18. doi: 10.1161/CIRCULATIONAHA.114.008750

  • CrossRef
  • Google Scholar

• 212

  FarrarEJHiriartEMahmutAJaglaBPealDSMilanDJet al. OCT4-mediated inflammation induces cell reprogramming at the origin of cardiac valve development and calcification. Sci Adv (2021) 7:eabf7910. doi: 10.1126/sciadv.abf7910

  • CrossRef
  • Google Scholar

• 213

  YaoYJumabayMLyARadparvarMCubberlyMRBostromKI. A role for the endothelium in vascular calcification. Circ Res (2013) 113:495–504. doi: 10.1161/CIRCRESAHA.113.301792

  • CrossRef
  • Google Scholar

• 214

  YaoJWuXQiaoXZhangDZhangLMaJAet al. Shifting osteogenesis in vascular calcification. JCI Insight (2021) 6 (10):e143023. doi: 10.1172/jci.insight.143023

  • CrossRef
  • Google Scholar

• 215

  XuDLiYZhangBWangYLiuYLuoYet al. Resveratrol alleviate hypoxic pulmonary hypertension via anti-inflammation and anti-oxidant pathways in rats. Int J Med Sci (2016) 13:942–54. doi: 10.7150/ijms.16810

  • CrossRef
  • Google Scholar

• 216

  AndreakosE. Targeting cytokines in autoimmunity: New approaches, new promise. Expert Opin Biol Ther (2003) 3:435–47. doi: 10.1517/14712598.3.3.435

  • CrossRef
  • Google Scholar

• 217

  Hernandez-SanchezJHarlowLChurchCGaineSKnightbridgeEBunclarkKet al. Clinical trial protocol for TRANSFORM-UK: A therapeutic open-label study of tocilizumab in the treatment of pulmonary arterial hypertension. Pulm Circ (2018) 8:2045893217735820. doi: 10.1177/2045893217735820

  • CrossRef
  • Google Scholar

• 218

  ZamanianRTBadeschDChungLDomsicRTMedsgerTPinckneyAet al. Safety and efficacy of b-cell depletion with rituximab for the treatment of systemic sclerosis-associated pulmonary arterial hypertension: A multicenter, double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med (2021) 204:209–21. doi: 10.1164/rccm.202009-3481OC

  • CrossRef
  • Google Scholar

• 219

  ToshnerMChurchCHarbaumLRhodesCVillar MoreschiSSLileyJet al. Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension. Eur Respir J (2022) 59(3):2002463. doi: 10.1183/13993003.02463-2020

  • CrossRef
  • Google Scholar

• 220

  HudallaHMichaelZChristodoulouNWillisGRFernandez-GonzalezAFilatavaEJet al. Carbonic anhydrase inhibition ameliorates inflammation and experimental pulmonary hypertension. Am J Respir Cell Mol Biol (2019) 61:512–24. doi: 10.1165/rcmb.2018-0232OC

  • CrossRef
  • Google Scholar