The actin cytoskeleton is a complex and dynamic intracellular structure that gives mechanical rigor to the cell while simultaneously mediating the transduction of mechanical stress into biochemical signals. Given the unique contractile properties of cardiac and vascular cells, the actin cytoskeleton is most essential to their integrity (Allahverdian et al., 2018; Zhang et al., 2018). Alteration of cytoskeletal organization, specifically actin filament dynamics, can result in gene expression and cell proliferation modification with the subsequent adaptation of and changes to intracellular biochemical responses and cellular functions, respectively. Thus, cytoskeletal remodeling can mediate mechanical stress-induced gene expression, cell proliferation, and pathological processes (Ohashi et al., 2017; Martino et al., 2018). Recent studies have shown that PIPs regulate cytoskeletal arrangement and signaling dynamics (Di Paolo and De Camilli, 2006; Saarikangas et al., 2010; Senju and Lappalainen, 2019). Specifically, PIP₂ is involved in cytoskeletal reorganizational events, including vesicle trafficking, cell migration, phagocytosis, and membrane cytoskeletal adhesion (Saarikangas et al., 2010; Shewan et al., 2011; Dickson and Hille, 2019; Phan et al., 2019). PIP₂ binds to and affects actin-binding proteins, such as myristoylated alanine-rich C kinase substrate (MARCKS), cofilin, gelsolin, α-actinin, Wiskott-Aldrich syndrome protein (WASP), and the Rho family of small GTPases (Janmey et al., 2018; Figure 2). MARCKS is an actin-binding protein found in mammalian tissues and, upon phosphorylation, it binds reversibly to structural and regulatory molecules in the cell in which there is an associated decrease in PIP₂ binding (Nairn and Aderem, 1992; Sheetz et al., 2006). Additionally, in vascular endothelial cells (ECs), MARCKS directly modulates PIP₂-mediated insulin signaling. The treatment of vascular ECs with insulin increases the levels of PIP₂, which is also released into lipid rafts (caveolar and non-caveolar fractions) to bind to the cytoskeletal protein, N-WASP. Subsequently, N-WASP phosphorylation and interaction with actin-related proteins 2/3 (Arp2/3) cause cytoskeletal remodeling to induce cell migration (Kalwa and Michel, 2011). Furthermore, MARCKS mediates a PIP₂-dependent actin rearrangement process. In this process, when low levels of MARCKS are present, actin filaments form an actin gel. Conversely, actin filaments aggregate upon increased levels of MARCKS. In the plasma membrane, the overall PIP₂ levels are relatively constant; however, changes in PIP₂ levels can be observed locally in the membrane directly overlying actin protrusions and membrane ruffles (Sheetz et al., 2006).

Rac, a downstream small GTPase effector, is a regulator of membrane ruffles (Ridley, 1994). In addition, Rac is instrumental to the transduction of external mechanical stimuli (Labouesse, 2011; Lawson and Burridge, 2014; McGowan and McCoy, 2017), including the mechanotransduction of the FAK-Cas-Rac axis, which transmits ECM stiffness into intracellular stiffness and mechanosensitive cell cycling (Bae et al., 2014). Moreover, PIP₂ levels fluctuate in membrane ruffles in a Rac-dependent manner. Although the immediate relationship of PIP₂ and Rac has not been explored in the context of cardiovascular biology and disease specifically, acknowledging their possible connection could better aid the understanding of their effects in different cellular pathways and help implicate PIP₂ as a Rac-mediated effector in vascular pathology (Polacheck et al., 2017; Narumiya and Thumkeo, 2018).

In striated muscle, capping protein Z (CapZ), an actin-capping protein, regulates cytoskeletal remodeling (Edwards et al., 2014). CapZ’s relationship with PIP₂ (Figure 3) has been recently observed in relation to mechanical stiffness and cytoskeletal remodeling, and the PIP₂-mediated interaction with CapZ has been shown to regulate cardiac myocyte hypertrophy (Li et al., 2016) and actin dynamics (Li and Russell, 2013). More specifically, ECM stiffening induces cardiac myocyte hypertrophy by increased PIP₂ localization at the sarcomere Z-discs in cardiac myocytes (Li et al., 2016). The Z-disc is a critical site for mechanotransduction and the location of the β1-isoform of CapZ (CapZβ1) (Russell et al., 2010). Moreover, the localization of PIP₂ to the sarcomere Z-disc is crucial to ventricular cardiac myocyte mechanotransduction and associated with pathological hypertrophic remodeling. Dysregulation of PIP₂ signaling alters sarcomere integrity by modulating the function of CapZβ1 and actin dynamics. Taken together, PIP₂ is vital to cardiac cell physiology, where it regulates CapZβ1 and actin dynamics in response to mechanical stimuli. Additionally, mechanical stimulation causes the production of PIP₂, specifically through the RhoA/Rho-associated kinase (ROCK) pathway (Li and Russell, 2013). Solís et al. explored PIP₂ signaling effects on CapZ through neomycin, a PIP₂ sequestering agent, in neonatal ventricular cardiomyocytes cultured on varying substrate stiffnesses. Further studies have assessed the molecular mechanisms by which different mechanotransduction signaling pathways mediate the capping and uncapping of CapZ from actin filaments via PIP₂. The results showed that interactions between PIP₂ and the β-tentacle of CapZ after molecular stimulation become considerably modified by phosphorylation. Moreover, CapZ is bound tightly to actin when inactive; however, upon phosphorylation and activation in growth states of hypertrophy, the binding is loosened. This is triggered by external stimuli, including mechanical flexing, loading, a stiffer substrate, angiotensin II, and phenylephrine. CapZ is modified by the stimuli’s signaling pathways through phosphorylation, acetylation or PIP₂ binding. Thus, an actin assembly mechanism can be presented where phosphorylation, acetylation or PIP₂ anchorage causes CapZ to act as a nodal terminus for the integration of various signaling pathways (Solis and Russell, 2019). This mechanism implicates PIP₂ as a critical mediator of mechanotransduction in cardiac myocytes by directly affecting CapZ in response to mechanical stiffness.

Phospholipase C (PLC) is a critical membrane-associated enzyme that, when stimulated by Gαq/11 subtype protein-coupled receptors (GαqPCRs), catalyzes the hydrolysis of PIP₂ phosphodiester bonds to generate inositol 1,4,5-triphosphate (IP₃) and diacylglycerol (DAG), which further activates PKC. These secondary messengers and downstream effector proteins are important for cardiovascular cell functions because they orchestrate the regulation of intracellular calcium mobilization, which is critical not only to the contractile apparatus but also to cell survival, proliferation, and differentiation. Plasma membrane store-operated channels (SOCs), particularly transient receptor potential canonical channels 1, 3, and 6 (TRPC1/3/6) and calcium release-activated calcium (CRAC), also called Orai 1, 2, and 3, are activated as a consequence of PLC activation (Abdullaev et al., 2008; Baudel et al., 2020; Wang et al., 2020). Vascular smooth muscle cell (VSMC) contraction, proliferation, and migration are regulated by the stimulation of SOCs at the plasma membrane and their associated Ca²⁺ influx pathways (Baudel et al., 2020). Moreover, these cellular behaviors are associated with the development of diseases of the vasculature, such as hypertension and atherosclerosis (Baudel et al., 2020). In VSMCs, PKC activity and PIP₂ are important in the activation pathway of SOCs, particularly transient receptor potential canonical channel 1 (TRPC1) (Saleh et al., 2009b; Shi et al., 2012; Baudel et al., 2020). Upon Ca²⁺ store depletion, TRPC1 is phosphorylated by PKC, which itself is stimulated by the PLC-PIP₂-DAG pathway (Saleh et al., 2009a), thus establishing a potentially direct link between TRPC1 and PIP₂. Additionally, TRPC1 is known to be an essential component of various mechanotransduction pathways, specifically in cells where TRPC1 is crucial for mechanosensitive cell migration (Formigli et al., 2009; Garrison et al., 2012; Canales et al., 2019; Li et al., 2019). Interestingly, TRPC1 is upregulated in pathological neointima remodeling in vessels induced by vascular injury, further suggesting that the induction of these channels is mechanosensitive (Kumar et al., 2006). Recent findings by Nikolaev et al. have suggested that the TRP ion channel superfamily is involved in a wide variety of mechanosensory processes, yet it has been shown that such channels are insensitive to tension induced by cell membrane stretching. Thus, although several TRP channels, including TRPC1, are essential components of mammalian stretch-activated mechanosensitive calcium-permeable cation channel heterologous systems, their true role in mechanotransduction remains unclear (Gottlieb et al., 2008). It is quite plausible that these ion channels are more likely to be activated by upstream components and consequently act as amplifiers of cellular mechanosensory signaling cascades, including PLC and PKC (Nikolaev et al., 2019). In addition to TRPC, the Orai channel, or CRAC, is another class of Ca²⁺-selective SOC activated as a consequence of PLC activation and subsequent PIP₂ depletion (Abdullaev et al., 2008; Baudel et al., 2020; Wang et al., 2020). This channel is expressed in VSMCs and upregulated in such cells in vascular pathologies, including vascular injury and restenosis, which are known to be mechanically mediated (Wang et al., 2008; Spinelli and Trebak, 2016). Previous reports have shown that Orai interacts with TRPC channel subtypes, including TRPC3 and TRPC6 (Liao et al., 2007); however, TRPC 1 is independent of Orai function (DeHaven et al., 2009; Shi et al., 2017). Although these two proteins share great similarity in their functionality, it has yet to be explored how they may be coupled mechanically. Previous studies have assessed the mechanosensitivity of the Orai channel; however, it remains to be empirically determined (Dong et al., 2019). Furthermore, Piezo1 is a recently characterized putative mechanically activated calcium permeable cation channel that is ubiquitously expressed through the cardiovascular system (Beech and Kalli, 2019). It has been uniquely shown that Piezo1’s mechanosensitivity to membrane tension is regulated by PIP₂ levels. Upon activation of TRPV1, PLC is activated and depletes the local levels of PIP₂, which subsequently inhibits Piezo1’s mechanosensitive activity (Borbiro et al., 2015).

The capillary endothelial cell (cEC) inward rectifier K⁺ channel Kir2.1 is critical to sensing and translating neural activity and neurovascular coupling in brain cECs (Longden and Nelson, 2015). This process of capillary-to-arteriole signaling in cECs is regulated by PIP₂. Moreover, PIP₂ levels are required for sustained Kir2.1 activity, and such regulation of Kir2.1 channels mediates electrical signaling during neurovascular coupling (Harraz et al., 2018a). More specifically, GαqPCRs stimulate PLC to rapidly either deplete or decrease PIP₂ levels and subsequently suppresses Kir2.1 channel signaling (Harraz et al., 2018a). This depletion of PIP₂ also promotes the activation of transient receptor potential vanilloid 4 (TRPV4), a channel found in cECs that is inhibited by PIP₂ under basal conditions and because of GαqPCR activation (Harraz et al., 2018b). Furthermore, PIP₂ levels govern capillary-to-arteriole electrical signaling by modulating the activity of TRPV4 and Kir2.1, which regulate the cellular states of depolarization and hyperpolarization. Thus, the levels of PIP₂ considerably modulate the magnitude of electrical signaling across cerebral capillaries, which ultimately affects cerebral microcirculatory blood flow in cECs (Harraz et al., 2018a,b). The relationship of TRPV4 to PIP₂ is important given TRPV4’s involvement in shear stress mechanotransduction in endothelial cells and mesenchymal cells and its ability to act mechanosensitively (Kohler and Hoyer, 2007; Yin and Kuebler, 2010; Corrigan et al., 2018). Therefore, the role of PIP₂ in this signaling pathway and its interaction with a known mechanotransducer, TRPV4, suggests that PIP₂ itself acts in the mechanotransduction of capillary electrical signaling.

Phosphatidylinositol-4-phosphate 5-kinase (PIP5K) phosphorylates the fifth position of the inositol head of phosphatidylinositol-4-phosphate. The type 1 PIP5K subfamily comprises three isoforms, Iα, Iβ, and Iγ, and is critical to many cytoskeletal processes. It has been reported that the overexpression of these isoforms induces the formation of stress fibers, membrane ruffles, and microvilli and regulates actin cytoskeletal dynamics, suggesting that this enzyme and its PIP₂ products are mechanosensitive (Chatah and Abrams, 2001). Weernink et al. reported that RhoA and its kinase, ROCK, which are both dominant effectors of mechanotransduction, are essential regulators of PIP5K in HEK-293 cells. The overexpression of ROCK enhances the PIP5K activity and subsequently elevates PIP₂ formation. Conversely, the chemical inhibition of ROCK decreases PIP5K activity and PIP₂ formation (Oude Weernink et al., 2000). Furthermore, Weernink et al. examined Type 1 PIP5K through other Rho family small GTPases, including Rac1 and Cdc42. Rho GTPases, RhoA, Rac1, and Cdc42 all mediate the PIP5K levels and lead to an increase in PIP₂ levels (Weernink et al., 2004). Therefore, PIP5K activity is RhoA-dependent in which signals from RhoA to the actin cytoskeleton are mediated, and synthesis of PIP₂ is enhanced (Oude Weernink et al., 2000).

The PIP₂ synthesis pathway in platelets through the isoform PIP5K Iα was more closely studied by Chatah and Abrams (2001) and Trepat et al. (2005). Thrombin, a known mediator of actin cytoskeleton remodeling (Chatah and Abrams, 2001; Trepat et al., 2005), promotes PIP₂ synthesis by PIP5K from PI4P in response to G protein-coupled receptor stimulation. PIP5K Iα localizes in the Golgi under basal conditions. Following stimulation of PAR1, a thrombin receptor, or overexpression of the active variant of Gα_q, PIP5K Iα relocates to the plasma membrane. This translocation of PIP5K Iα is dependent on Rac1 and RhoA. Rac1 has been suggested to affect PIP5K indirectly, and activation is required by Rho (Chatah and Abrams, 2001).

Although these studies independently identified Rho GTPases in mediating PIP5K activity, the mechanisms by which Rho GTPase is suggested to activate PIP5K are separate. Taken together, these findings indicate that members of the Rho GTPase family, RhoA, Rac, and Cdc42, are vital in mediating PIP5K activation and, consequently, PIP₂ synthesis, regardless of their interconversional crosstalk (Oude Weernink et al., 2000; Chatah and Abrams, 2001; Weernink et al., 2004). Furthermore, these GTPases act as a dynamic molecular switch between various cells, which play a key role in vascular pathology (Cai et al., 2015; Karoor et al., 2018; Barlow and Cleaver, 2019) and are involved in mechanosensing and mechanotransduction pathways (Verma et al., 2011; Chaterji et al., 2014; Zegers and Friedl, 2014; Ohashi et al., 2017). The relationship of PIP5K with small downstream GTPases in vascular pathology and mechanotransduction has not yet been explored. Due to the relevance of the small GTPases Rho, Rac, and Cdc42 for PIP5K activity and PIP₂ synthesis, this pathway may be vitally important for better understanding vascular disease and may be potentially significant in the overall study of mechanotransduction in the context of vascular pathology. Therefore, the relationship of these PIP5Ks and these downstream GTPases should be explored in relation to mechanotransduction and vascular disease.

Phosphoinositide 3-kinase (PI3K) is a family of evolutionarily conserved lipid kinases that mediate many cellular responses to physiological and pathophysiological stimuli. The PI3K family is divided into three subgroups (classes I, II, and III), which together include eight isoforms. The class I isoforms, PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ, convert PIP₂ to phosphatidylinositol-3,4,5-triphosphate (PIP₃) (Vanhaesebroeck et al., 2010; Miller et al., 2019). Activated PI3K produces PIP₃, which further recruits 3-phosphoinositide-dependent kinase 1 (PDK1) to the plasma membrane (Hagiwara et al., 2012). PIP₃ activates PDK1 through its PH domain. PDK1 subsequently phosphorylates and activates Akt at threonine residue 308 (T308) (Ghigo and Li, 2015; Manning and Toker, 2017). More importantly, the phosphorylation of serine residue 473 (S473) by the mechanistic target of the mammalian target of rapamycin complex 2 (mTORC2) stabilizes not only T308 phosphorylation but also AKT in its active state (Manning and Toker, 2017). Together, Akt and PI3K create a unique signaling pathway (Akt/PI3K) that is instrumental in cardiomyocyte mechanotransduction (Li C.J. et al., 2019). Moreover, the Akt/PI3K signaling pathway regulates intracellular and extracellular activities in response to mechanical stress and molecular effectors, leading to a robust cellular mechanotransduction signaling cascade in cardiac myocytes. These cellular responses include modulation of cell metabolism, growth, proliferation, angiogenesis, and cardiac adaptation (Aoyagi and Matsui, 2011; Markowska et al., 2014; Yang et al., 2018). In a disease model, chronic activation of the Akt/PI3K pathway dysregulates cell contractility, which induces compensatory cardiac hypertrophy with preserved contractility and ultimately advances to chronic dilated cardiomyopathy (Shiojima et al., 2005; Li C.J. et al., 2019). Furthermore, alterations in the function and structure of titin, a giant sarcomeric filament protein, have been observed in similar cardiomyopathies, including cardiac remodeling, hypertrophy, and heart failure (Linke, 2008; Kruger and Linke, 2009; Lyon et al., 2015). In cardiac sarcomeres, titin isoforms exhibit varying properties of mechanical elasticity and are differentially expressed throughout cardiac development and during disease in which isoform switching is dynamically regulated by the Akt/PI3K signaling pathway (Kruger and Linke, 2009). Moreover, it is believed that these properties of titin are uniquely positioned to serve as a molecular sensor of mechanical stress in cardiac myocytes, including oscillatory changes in cell stretching known to induce PI3K activation through molecular mechanisms that remain unclear (Miller et al., 2004; Linke, 2008; Leychenko et al., 2011; Voelkel and Linke, 2011).

In cardiac myocytes, mechanotransduction critically mediates remodeling of the cytoskeleton, and dysregulation of this process can drive heart disease in response to aberrant biomechanical stress. Biomedical research on patients with hypertension has revealed how critical cardiac mechanotransduction plays in this response (Patel et al., 2013). One study by Patel et al. demonstrated that PI3Kα, a major PI3K isoform in the heart, negatively regulates gelsolin activity and suppresses pathological cytoskeletal remodeling in response to biomechanical stress-induced cardiac mechanotransduction and the resulting dilated cardiomyopathy (Guo et al., 2010). Similarly, a separate study showed that loss of PTEN in ventricular cardiac myocytes increases PI3Kα activity, which attenuates pressure overload-induced heart failure but loss of myocardial contractility (Oudit et al., 2008). Conversely, however, other studies have shown that constitutively activated PI3K drives the growth and hypertrophy of such cells, greatly increasing the heart size in mice, while knocking down PI3Kα results in mice with smaller hearts (Shioi et al., 2000). In response to mechanical stress, PI3Kα translocates to the plasma membrane to convert PIP₂ to PIP₃, which subsequently recruits gelsolin to the plasma membrane (Patel et al., 2018). A resulting spatial colocalization occurs between p110α, the catalytic subunit of PI3Kα, and gelsolin in which p110α-catalyzed PIP₃ negatively regulates gelsolin activity and thus diminishes unfavorable remodeling of the actin cytoskeleton while conserving the cytoskeletal integrity. Consequently, PI3Kα-generated PIP₃ plays a critical role in the mechanotransduction of cardiomyocytes by negatively regulating gelsolin, which subsequently inhibits actin remodeling (Patel et al., 2018).

In cardiac myocytes, GPCRs activate PI3Kγ in response to pressure overload or biomechanical stress, which mediates the adaptive role in cardiac mechanotransduction by negatively regulating cyclic adenosine monophosphate (cAMP) levels (Guo et al., 2010). It was first shown that complete deletion of PI3Kγ in cardiac myocytes alters heart function by inducing cell hypercontractility as a result of cAMP accumulation but does not alter the cell structure or growth (Crackower et al., 2002; Patrucco et al., 2004); however, a separate study has shown that deletion of PI3Kγ accelerates the development of pathological hypertrophy (Guo et al., 2010). Intriguingly, the regulation of cell contractility by PI3Kγ in response to mechanical stress is independent of its activity or functional kinase domain (Patrucco et al., 2004). More specifically, cardiac myocytes lacking PI3Kγ activity with preserved expression exhibit normal levels of cAMP that are believed to be the result of phosphodiesterase 3B positive regulation by a PI3Kγ-associated multifunctional protein complex (Patrucco et al., 2004). Critical to this complex is the anchoring of PKA to PI3Kγ and downstream activation of phosphodiesterases, type 3 and 4 (PDE3/4), and subsequently reducing the cAMP levels; upon its anchoring, PKA also phosphorylates and inhibits PI3Kγ lipid kinase activity, resulting in a reduction in PIP₃ (Perino et al., 2011; Ghigo et al., 2017). In pressure overload-mediated sympathetic overdrive of cardiac myocytes, the beta2 adrenergic receptor is desensitized and internalized as a result of PKA-escaped PI3Kγ kinase activity and ultimately induces hypokinetic dilated heart failure (Prasad et al., 2005; Perino et al., 2011; Ghigo and Li, 2015; Ghigo et al., 2017). Despite enhanced calcium dynamics and contractility upon the loss of PI3Kγ in cardiac myocytes, decompensation ensues because of dysregulated cellular-ECM interactions (Guo et al., 2010). Furthermore, a more direct relationship between PI3Kγ and cardiac mechanotransduction is observed upon the loss of PI3Kγ, in which elevated cAMP levels mediate extracellular matrix remodeling and interactions (Guo et al., 2010). In this particular instance, inhibiting the beta2 adrenergic receptor protects N-cadherin adhesion complexes from degradation (Guo et al., 2010), whereas the loss of p110γ function, the catalytic subunit of PI3Kγ, leads to heart failure by the deterioration of N-cadherin and an increase in cAMP levels (Patel et al., 2018). Furthermore, N-cadherin complexes actively perceive biomechanical stress, and through the regulation of gelsolin, actin polymerization is promoted, therefore expressing a collaborative relationship between PI3Kγ and PI3Kα in cardiac mechanotransduction (Chan et al., 2004).

The Hippo signaling pathway, which was originally observed in Drosophila, mediates the VSMC stretch response that inhibits cell proliferation and participates in mechanotransduction pathways (Huang et al., 2005; Ota and Sasaki, 2008; Yu et al., 2015; Chakraborty et al., 2017; Fletcher et al., 2018). Inhibition of the Hippo pathway promotes tissue growth in epithelial cells through the PI3K-PDK1-Akt axis upon mechanical stimulation and growth factor signaling (Borreguero-Munoz et al., 2019). Yes-associated protein 1 (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) are downstream transcriptional activators of the Hippo pathway (Halder et al., 2012). These effectors are regulated by mechanical cues, specifically, matrix stiffness, stretch, and cell density, which influence cell proliferation and differentiation (Halder et al., 2012; Codelia et al., 2014; Meng et al., 2016). Thus, YAP and TAZ function as essential effectors of mechanotransduction (Meng et al., 2018). YAP/TAZ-dependent glutaminolysis and anaplerosis are mechanoactivated by vascular stiffness to drive cell proliferation in pulmonary hypertension (Bertero et al., 2016). Additionally, mechanical stretching regulates YAP/TAZ activity via the PI3K-PDK1-mediated pathway in human umbilical arterial VSMCs (Wang et al., 2018). Furthermore, the PDK1 interaction with the Hippo complex is mediated through Sav1, where PDK1 directly controls the Hippo pathway (Wang et al., 2018). The consequential association of PI3K with the Hippo signaling pathway effectors YAP and TAZ in vascular cells further implicates PI3K in the mechanotransduction of the cardiovascular system.

Mechanical forces of a hemodynamic nature are uniquely fundamental for vascular homeostasis as well as pathological vascular remodeling that are commonly observed in CVD (Cahill and Redmond, 2016; Russo et al., 2018). In cells of the vasculature, harmony in cell proliferation, apoptosis, migration, and differentiation is integral to vascular wall homeostasis. Mechanical forces perceived by ECs and VSMCs generate a biological response, i.e., mechanotransduction to induce physiological vascular remodeling (Qi et al., 2018). Consequently, vascular remodeling involves a variety of cellular components to mediate these biophysical and biochemical events, including PI3K, which has previously been connected to the vascular remodeling pathway. During angiogenesis, vessel remodeling can help with cell proliferation and maturation (Wang and Khalil, 2018). Vascular remodeling in pericytes is regulated by PI3Kβ. Mature pericytes, which are mostly found in vessels undergoing remodeling, are quiescent and express low activation of the PI3K signaling. Inactivation of PI3Kβ in these cells generates early pericyte maturation, with an increase in PI3K signaling that obstructs pericyte maturation. Thus, pericytes in a sustained immature state will result in vascular hyperplasia and block vascular remodeling, whereas accurate PI3K signaling is necessary for pericyte maturation and correct vessel formation (Figueiredo et al., 2020).

One of the most prevalent cardiovascular diseases involving vascular remodeling is atherosclerosis. During atherosclerosis, vascular injury occurs, causing abnormal proliferation of VSMCs, which leads to neointima formation and vessel lumen narrowing and ultimately limits blood flow and oxygen supply (Yu et al., 2018). PI3K has been directly associated with the molecular pathways that mediate vascular remodeling and atherosclerosis. The catalytic subunit of PI3Kα, p110α, is important for receptor tyrosine kinase (RTK) signaling, which is upstream of class 1A PI3K isoforms, in VSMCs. Furthermore, p110α is critical to neointima formation after balloon angioplasty by mediating VSMC proliferation and migration, while the PI3Kα isoforms p100β and p110δ do not play a significant role (Vantler et al., 2015).

PI3Kγ functions in both leukocytes and cardiomyocytes and plays a role in atherosclerosis and heart disease. PI3Kγ controls leukocyte infiltration in the myocardium and arteries. PI3Kγ is involved in neuraminidase-1 (Neu-1) signaling, which governs atherosclerosis development (Gayral et al., 2014). Genetic and pharmacological inhibitory targeting of PI3Kγ in leukocytes reduces atherosclerosis in mouse models (Fougerat et al., 2008). Ghigo et al. (2017) recently reviewed PI3K and calcium signaling in cardiovascular disease. The PI3K pathway has recently been interconnected with Ca²⁺ signaling. PI3Kγ appears to be preferentially linked to Ca²⁺ signaling in smooth muscle cells (Lupieri et al., 2020), where Class I PI3Ks are highly expressed. This interconnection between the PI3Kγ pathway and Ca²⁺ signaling has been involved in smooth muscle cell proliferation and migration, atherosclerosis and arterial injury. The development of arterial lesions through various immune functions requires PI3Kγ activity with PI3Kγ playing an important role in arterial injury in T cells. For example, it has been found that PI3Kγ regulates T-cell function, and it has been proposed that PI3Kγ interacts with Ca²⁺ signaling, leading to Ca²⁺ influx downstream of T-cell receptor activation; thus, PI3Kγ interconnects with Ca²⁺, playing an important role in arterial injury (Smirnova et al., 2014; Lupieri et al., 2015; Ghigo et al., 2017). Taken together, PI3Kβ and PI3Kγ are paramount pathways that drive cardiovascular remodeling seen in heart failure as well as in atherosclerosis, and this strongly suggests that PI3K is critically involved in mechanotransduction-mediated cardiovascular disease.