Vascular Smooth Muscle Cells and Arterial Stiffening: Relevance in Development, Aging, and Disease

Abstract

The cushioning function of large arteries encompasses distension during systole and recoil during diastole which transforms pulsatile flow into a steady flow in the microcirculation. Arterial stiffness, the inverse of distensibility, has been implicated in various etiologies of chronic common and monogenic cardiovascular diseases and is a major cause of morbidity and mortality globally. The first components that contribute to arterial stiffening are extracellular matrix (ECM) proteins that support the mechanical load, while the second important components are vascular smooth muscle cells (VSMCs), which not only regulate actomyosin interactions for contraction but mediate also mechanotransduction in cell-ECM homeostasis. Eventually, VSMC plasticity and signaling in both conductance and resistance arteries are highly relevant to the physiology of normal and early vascular aging. This review summarizes current concepts of central pressure and tensile pulsatile circumferential stress as key mechanical determinants of arterial wall remodeling, cell-ECM interactions depending mainly on the architecture of cytoskeletal proteins and focal adhesion, the large/small arteries cross-talk that gives rise to target organ damage, and inflammatory pathways leading to calcification or atherosclerosis. We further speculate on the contribution of cellular stiffness along the arterial tree to vascular wall stiffness. In addition, this review provides the latest advances in the identification of gene variants affecting arterial stiffening. Now that important hemodynamic and molecular mechanisms of arterial stiffness have been elucidated, and the complex interplay between ECM, cells, and sensors identified, further research should study their potential to halt or to reverse the development of arterial stiffness.

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

“…We have also observed an age‐related increase in ex vivo activated smooth muscle stiffness of the mouse 16. Indeed, there is now a significant amount of evidence from multiple laboratories to suggest that the smooth muscle cell contributes significantly to the development of age‐related increases in active aortic stiffness 16, 17, 18, 19, 20, 21, 22, 49, 50. Our findings point to the FA complex and the attached, nonmuscle actin cytoskeleton as key sources for the increase in smooth muscle cell stiffness.…”

“…However, it has also been proposed that aging of the vascular smooth muscle cell (VSMC) can adversely modulate the fractional engagement of collagen, leading to a dynamic increase in stiffness 16, 17, 18, 19, 20, 21, 22. In fact, recent studies in a mouse model, where viable smooth muscle preparations can be readily obtained and activated with vasoactive agents to measure active stiffness, have demonstrated that close to half of the total stiffness of the aortic wall is attributable to the active stiffness of the VSMC,16 with the remaining fraction due to the extracellular matrix.…”

Potential Role of Antihypertensive Medications in Preventing Excessive Arterial Stiffening

“…For example, VSMCs in Zucker obese insulin resistant rats manifest greater concentrations of reactive oxygen species (ROS), impaired activation of the NO/cyclic guanosine monophosphate/protein kinase G pathway, and increased cell stiffness [15]. VSMCs are capable of osteoblast trans-differentiation by promoting alkaline phosphatase activity, the formation of mineralized nodules, and osteocalcin expression in VSMCs [16]. Thus, VSMC calcification is another important contributor in the development of excessive arterial stiffness.…”

Bordeaux Viva Winter School - Xxxiii Liac Meeting

“…This will also influence vascular smooth muscle cells (VSMC) to undergo changes as the VSMC contractile phenotype is associated with an increased arterial stiffness. This can take place both in the arterial media and the adventitia [1]. In addition, some specific processes related to the adventitia may further increase stiffness.…”

“…Michel Spina Following population aging and due to congenital and acquired diseases the annual number of patients requiring heart valve replacement worldwide has been estimated to triple from approximately 290,000 in 2003, to over 850,000 by 2050 [1]. Prosthetic heart valves are broadly divided in mechanical heart valves (MHV) and bioprosthetic heart valves (BHV) while ≈55% are MHVs and ≈45% BHVs [2] not taking into account most recent transcatheter heart valves.…”