Edited by: Olivier M. Vanakker, Ghent University Hospital, Belgium
Reviewed by: Ying Xu, West Virginia University, USA; Wei Zhang, University of Michigan, USA
*Correspondence: Leon J. Schurgers, Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, PO Box 616, 6200 MD Maastricht, Netherlands. e-mail:
This article was submitted to Frontiers in Systems Biology, a specialty of Frontiers in Genetics.
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Vascular disease is still the leading cause of morbidity and mortality in the Western world, and the primary cause of myocardial infarction, stroke, and ischemia. The biology of vascular disease is complex and still poorly understood in terms of causes and consequences. Vascular function is determined by structural and functional properties of the arterial vascular wall. Arterial stiffness, that is a pathological alteration of the vascular wall, ultimately results in target-organ damage and increased mortality. Arterial remodeling is accelerated under conditions that adversely affect the balance between arterial function and structure such as hypertension, atherosclerosis, diabetes mellitus, chronic kidney disease, inflammatory disease, lifestyle aspects (smoking), drugs (vitamin K antagonists), and genetic abnormalities [e.g., pseudoxanthoma elasticum (PXE), Marfan's disease]. The aim of this review is to provide an overview of the complex mechanisms and different factors that underlie arterial remodeling, learning from single gene defect diseases like PXE, and PXE-like, Marfan's disease and Keutel syndrome in vascular remodeling.
Arterial remodeling refers to the myriad of structural and functional changes of the vascular wall that occur in response to disease, injury, or aging. Although arterial remodeling can be regarded as a mechanism that naturally occurs with aging, early arterial remodeling is associated with significant hemodynamic changes and cardiovascular morbidity and mortality. Arterial remodeling is set into motion by a variety of complex pathophysiological mechanisms that are closely interrelated, and that influence both the cellular and non-cellular components of the vascular wall. Mechanisms involved in arterial remodeling include fibrosis, hyperplasia of the arterial intima and media, changes in vascular collagen and elastin, endothelial dysfunction, and arterial calcification. Migration and proliferation of vascular smooth muscle cells (VSMCs) contribute to thickening of the arterial intima. Differentiation of VSMCs from their contractile to a secretory or osteogenic phenotype may lead to increased vascular tone, and promotes extracellular matrix (ECM) calcification. Additionally, alterations in the activity of vitamin K-dependent proteins may affect the progression of vascular remodeling, including the induction of calcification. Because of this complexity, it is difficult to study to what extent a single mechanism contributes to arterial remodeling. Monogenetic diseases such as pseudoxanthoma elasticum (PXE), PXE-like syndrome, Marfan's syndrome or Keutel syndrome are characterized by a clinical phenotype that is similar to that of arterial remodeling, but are caused by a specific defect that affects only one or several pathophysiological mechanisms of arterial remodeling. Lessons learned from these relatively rare diseases may therefore ultimately provide insight in more common, multifactorial cardiovascular diseases such as hypertension, diabetes mellitus, and chronic kidney disease as well as in normal vascular aging.
Arterial remodeling is thought to reflect adaptation of the vessel wall to mechanical and hemodynamic stimuli (Nichols and O'Rourke,
Thickening of the arterial wall is caused by intimal hyperplasia, medial hypertrophy and hyperplasia of VSMCs, and deposition of ECM material including minerals (Virmani et al.,
In addition to structural changes, endothelial function plays an important role in arterial remodeling. Blood flow and shear stress stimulate endothelial cells to produce nitric oxide (NO), which in turn influences contraction and relaxation of VSMCs. Endothelial function decreases with age and endothelial dysfunction is common in many cardiovascular diseases. Moreover, in response to pathological conditions, such as altered shear stress or inflammation, endothelial cells produce cytokines and growth factors that influence the homeostasis of the vascular wall (Csiszar et al.,
Arterial remodeling is driven by numerous, highly regulated and interrelated processes. Processes that are of particular importance as they are central in arterial remodeling include: (1) VSMC proliferation and differentiation, (2) degradation and fracture of elastin fibers, and (3) calcification and deposition of ECM material (Figure
VSMCs are key regulators of vascular tone and health and insight into their function is of utmost importance for our understanding of the causes of arterial remodeling. In normal arteries, VSMCs in the tunica media regulate vessel tone and diameter in order to maintain hemodynamic balance (Alexander and Owens,
Phenotype switching occurs in response to vascular injury or stress and is characterized by reduced expression of genes which are specific for contractile VSMCs and cellular morphology (Alexander and Owens,
Inflammation |
Oxidative stress |
Hemodynamic shear stress |
Mechanical stretch |
Advanced glycation end products (AGE) |
Increased calcium-phosphate product |
Angiotensin II (Ang II) |
Aldosterone |
Transforming growth factor-β (TGF-β) |
Fibroblast growth factor (FGF) |
Endothelial growth factor (EGF) |
Platelet derived growth factor (PDGF) |
Matrix metalloproteinases (MMP) |
Synthetic VSMCs produce elastolytic enzymes (matrix metalloproteinases; MMPs), which facilitate migration by detaching cells from the basement membrane and ECM. Indeed, upregulation of MMPs coincides with the migration of VSMCs (Willis et al.,
Under specific stimuli such as sustained high extracellular levels of calcium and phosphate or in the absence of inhibitors of calcification, VSMCs can differentiate into an osteogenic phenotype in which VSMCs acquire features usually observed in chondrocytes and osteoblasts (Shanahan et al.,
Tanimura and co-workers were the first to report an association between small membrane encapsulated particles, MVs, and vascular calcification (Tanimura et al.,
Elastic fibers consist of polymers of tropoelastin cross-linked to fibrillin-rich microfibrils. In the vasculature, elastin is mainly produced during the fetal and neonatal period by (secretory) VSMCs. Above we discussed the importance of elastin for maintaining arterial wall stability and VSMC homeostasis in Marfan's Disease. Additionally, elastin is also an important nidus for calcification. This is illustrated in PXE disease and its accompanying clinical features. PXE is characterized by extensive calcification that mainly occurs along elastic fibers. Although cutaneous manifestations are primarily of cosmetic concern, presence of characteristic skin lesions signifies risk for development of vascular calcification with considerable morbidity and occasional early mortality (Uitto et al.,
Even in the absence of diseases which directly affect elastin structure and function, similar processes can be observed in vascular aging and aortic stiffening (Smith et al.,
Both VSMC phenotype switching and ECM degradation result in enhanced and accelerated vascular calcification. Initially, vascular calcification was regarded as passive mineral deposition. However, this view has been abandoned since overwhelming evidence exists that vascular calcification actually is a highly regulated process. Soft tissue calcification is thought to result from an imbalance between calcification-promoting and -inhibiting factors (Table
Bone morphogenetic protein 2 (BMP-2) |
↑ Calcium-phosphate product |
Tumor Necrosis Factor α (TNF-α) |
Interleukin 6 (IL-6) |
Receptor activator of nuclear factor κB (RANK) ligand (RANKL) |
Insulin-like growth factor I (IGF-I) |
Insulin |
↑ Glucose |
↑ Parathyroid hormone |
Matrix metalloproteinases (MMP) |
Elastin degradation |
Hydroxyapatite crystals |
Fetuin-A |
Matrix gla protein (MGP) |
Osteoprotegerin (OPG) |
In PXE, the underlying genetic defect is a loss-of-function mutation of the abcc6 gene. This gene encodes a transmembrane transporter protein (Multi Drug Resistant Protein 6; MDRP-6). The substrate of the MDRP-6 is not known, and the exact mechanisms by which this mutation leads to elastin calcification are not yet fully understood. Recent studies have pointed toward calcification being stimulated by phenotype switching of VSMCs, oxidative stress, and interference with carboxylation of MGP (Pasquali-Ronchetti et al.,
Since the normal function of vessels is to maintain adequate perfusion of organs and tissues and to buffer oscillating blood pressures, arterial remodeling results in changes in this function. At first, these are compensatory (i.e., reducing wall tension). However, in later stages these compensatory mechanisms become detrimental and initiate a vicious cycle of pathophysiological aberrations.
Fragmentation of the elastic lamina, hyperplasia and hypertrophy of VSMC, loss of contractility of VSMC, deposition of collagen, and arterial calcification lead to stiffening of arteries. Many studies have shown that arterial stiffness, which is clinically measured as the carotid-femoral pulse wave velocity (cfPWV), is independently associated with cardiovascular risk and mortality (Laurent et al.,
High blood pressure pulsatility leads to increased mechanical vascular wall stress. With high central PP, the amplitude in which the arterial wall expands and contracts with each consecutive heartbeat is increased. This leads to higher stretch on elastic and collagen fibers in the arterial wall and this in turn may contribute to material fatigue, fracture, and degradation. Additionally, cyclic stretching of VSMC has been demonstrated to stimulate phenotype switching and arterial remodeling (Williams,
Arterial stiffness and endothelial function not only stimulate the development of atherosclerotic plaques but also further promotes arterial media remodeling. In this way, arterial stiffness may explain the interrelationship of arteriosclerosis and atherosclerosis.
Finally, the pathological hemodynamic patterns due to arterial stiffness lead to damage of susceptible organs such as kidneys, brain, and heart. It has been established that arterial stiffness and chronic kidney disease are closely interrelated (Safar et al.,
In PXE, PXE-like syndrome as well as in Keutel's syndrome, arterial calcification is an important feature of the clinical phenotype. Besides these, arterial calcification is also observed in more common disorders such as diabetes, hyperparathyroidism, and chronic kidney disease as well as in vascular aging. In addition, vascular calcification may be induced by drugs that adversely affect the regulatory balance between factors inducing or inhibiting calcification. For instance, chronic treatment with vitamin K-antagonists (such as warfarin) is associated with peripheral artery calcification (Rennenberg et al.,
In addition to calcification, other pathophysiological pathways of arterial remodeling such as arterial stiffening, fibrosis, or elastin degradation may also be potential candidates for intervention. However, finding suitable, modifiable candidates has proven to be a challenge. Although most existing antihypertensive drugs may reduce arterial stiffness to some extent, it is difficult to determine whether this effect is mainly due to blood pressure reduction or represents a true effect on ECM remodeling (Boutouyrie et al.,
Studying genetic diseases such as PXE, PXE-like syndrome, Keutel's syndrome and Marfan's disease increase our knowledge about pathophysiological mechanisms underlying arterial remodeling (summarized in Figures
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.