The Role of Vascular Smooth Muscle Cells in Arterial Remodeling: Focus on Calcification-Related Processes

Abstract

Arterial remodeling refers to the structural and functional changes of the vessel wall that occur in response to disease, injury, or aging. Vascular smooth muscle cells (VSMC) play a pivotal role in regulating the remodeling processes of the vessel wall. Phenotypic switching of VSMC involves oxidative stress-induced extracellular vesicle release, driving calcification processes. The VSMC phenotype is relevant to plaque initiation, development and stability, whereas, in the media, the VSMC phenotype is important in maintaining tissue elasticity, wall stress homeostasis and vessel stiffness. Clinically, assessment of arterial remodeling is a challenge; particularly distinguishing intimal and medial involvement, and their contributions to vessel wall remodeling. The limitations pertain to imaging resolution and sensitivity, so methodological development is focused on improving those. Moreover, the integration of data across the microscopic (i.e., cell-tissue) and macroscopic (i.e., vessel-system) scale for correct interpretation is innately challenging, because of the multiple biophysical and biochemical factors involved. In the present review, we describe the arterial remodeling processes that govern arterial stiffening, atherosclerosis and calcification, with a particular focus on VSMC phenotypic switching. Additionally, we review clinically applicable methodologies to assess arterial remodeling and the latest developments in these, seeking to unravel the ubiquitous corroborator of vascular pathology that calcification appears to be.

Keywords: arterial remodeling; hypertension; phenotype switching; vascular calcification; vascular smooth muscle cell; vascular stiffness.

Figure 1

(a) Vascular smooth muscle cell (VMSC) phenotypic switching. Under physiological conditions, VSMCs display a contractile phenotype that regulates vessel structure and function. Under stress, arterial remodeling will occur, leading to VSMC phenotypic switching. Factors inducing the synthetic phenotype include platelet derived growth factors (PDGF), protease-activated receptors (PARs) and tumor necrosis factor-alpha (TNF-α). Synthetic VSMCs initiate vessel repair and can switch back to the contractile phenotype, driven by factors such as heparin or laminin. The osteogenic phenotype can be induced by prolonged exposure to BMP-2 or high phosphate. Osteogenic VSMCs shed extracellular vesicles that promote vascular calcification. Panel (b). Pathways affecting vascular calcification. Vascular calcification is an active process which can be initiated by several pathways, including: 1. biochemical factors, 2. physical factors, 3. vascular calcification (VC) inhibitors and 4. ECM factors. Biochemical factors, such as raised calcium and phosphate levels and PDGF, are stress molecules that induce VSMCs to switch towards a synthetic or osteogenic phenotype, including an increased release of extracellular vesicles. The ECM of the vessel wall directly influences VSMCs. Changes in collagen and elastin content cause VSMCs to change morphology and phenotype. VSMCs in turn, produce MMPs that induce structural changes in the vessel wall by rearranging collagen and elastin, promoting the migration and proliferation of VSMCs and other cell types. Physical factors such as shear stress and tensile stress affect ECs’ NO release, which influences the VSMC phenotype. Shear-induced stress induces a synthetic phenotype by decreasing a-SMA, MYH and smtn expression. Tensile stretch induces VSMCs to produce ECM proteins, such as collagen and fibronectin promoting vessel fibrosis. VC inhibitors, such as OPN, MGP and PP_1, affect the VSMC phenotype by inducing changes in RNA expression patterns. Taken together, all stimuli play a part in an orchestrated VSMC response, ultimately promoting vascular calcification.

Figure 1

(a) Vascular smooth muscle cell (VMSC) phenotypic switching. Under physiological conditions, VSMCs display a contractile phenotype that regulates vessel structure and function. Under stress, arterial remodeling will occur, leading to VSMC phenotypic switching. Factors inducing the synthetic phenotype include platelet derived growth factors (PDGF), protease-activated receptors (PARs) and tumor necrosis factor-alpha (TNF-α). Synthetic VSMCs initiate vessel repair and can switch back to the contractile phenotype, driven by factors such as heparin or laminin. The osteogenic phenotype can be induced by prolonged exposure to BMP-2 or high phosphate. Osteogenic VSMCs shed extracellular vesicles that promote vascular calcification. Panel (b). Pathways affecting vascular calcification. Vascular calcification is an active process which can be initiated by several pathways, including: 1. biochemical factors, 2. physical factors, 3. vascular calcification (VC) inhibitors and 4. ECM factors. Biochemical factors, such as raised calcium and phosphate levels and PDGF, are stress molecules that induce VSMCs to switch towards a synthetic or osteogenic phenotype, including an increased release of extracellular vesicles. The ECM of the vessel wall directly influences VSMCs. Changes in collagen and elastin content cause VSMCs to change morphology and phenotype. VSMCs in turn, produce MMPs that induce structural changes in the vessel wall by rearranging collagen and elastin, promoting the migration and proliferation of VSMCs and other cell types. Physical factors such as shear stress and tensile stress affect ECs’ NO release, which influences the VSMC phenotype. Shear-induced stress induces a synthetic phenotype by decreasing a-SMA, MYH and smtn expression. Tensile stretch induces VSMCs to produce ECM proteins, such as collagen and fibronectin promoting vessel fibrosis. VC inhibitors, such as OPN, MGP and PP_1, affect the VSMC phenotype by inducing changes in RNA expression patterns. Taken together, all stimuli play a part in an orchestrated VSMC response, ultimately promoting vascular calcification.

Figure 2

Vascular remodeling types. There are several types of arterial remodeling: hypotrophic, eutrophic and hypertrophic. Additionally, remodeling can be inward and outward. Hypotrophic remodeling results in a thinner vessel wall, which can be both inward and outward. In both cases, the wall-to-lumen ratio decreases. Hypertrophic remodeling results in the thickening of the vessel wall, that can also be inward and outward. The thickening of the vessel wall results in an increased wall-to-lumen ratio. In the eutrophic situation, wall-to-lumen ratios do not differ, but the size of the vessel can change. Atherosclerosis is characterized by an increased wall-to-lumen ratio, with both thickening of the media and intima and, therefore, is classified as inward or outward hypertrophic remodeling. Aneurysm formation is characterized by an increase in vessel diameter with a thinning of the vessel wall (outward hypotrophic remodeling). Inward remodeling is less frequent and is more associated with muscular peripheral arteries, reflecting sustained vasoconstriction of vessels.

Figure 3

Endothelial cell–smooth muscle cell communication. Endothelial cells (ECs) communicate with vascular smooth muscle cells (VSMCs) in two ways, called endothelial derived hyperpolarization (EDH). EDH has two major pathways: 1. Diffusion of nitric oxide (NO), which is produced by ECs and diffuses through the internal elastic lamina (IEL) to induce the relaxation of VSMCs. 2. Signaling through myoendothelial gap junctions (MEGJ) that connect ECs directly to VSMCs and cross the IEL. This direct communication between ECs and VSMC via MEGJ occurs via so-called endothelial derived hyperpolarizing factors (EDHF). 3. Major factors that stimulate EC NO secretion are flow or shear-stress alterations. Differences in wall shear rates are known to induce endothelial-derived changes in VSMC phenotype.