Mechanisms of arterial remodeling in hypertension: coupled roles of wall shear and intramural stress

Abstract

Hypertension causes and is caused by significant changes in the structure and function of arteries. Diverse data collected over the past four decades reveal that many of these changes result from a mechanical stress or strain mediated reorganization and turnover of cells and extracellular matrix in vasoaltered states that promotes a “mechanical homeostasis.” This paper reviews diverse data on the mechanobiological behaviors of vascular cells (endothelial, smooth muscle, and fibroblasts) and associated changes that manifest at the tissue level. Although experimental design is often motivated by the thought that altered flow largely affects arterial caliber and altered pressure largely affects wall thickness, all three primary descriptors of vessel geometry (radius, thickness, length) are coupled strongly to all three primary measures of stress (wall shear, circumferential, axial). Hence, mechanobiological responses by resident cells should likewise be expected to be sensitive to all three primary stresses. It also appears that cellular production of vasoactive molecules, growth factors, cytokines, matrix proteins, and proteases depends nonlinearly, often sigmoidally, on changes in stress. This suggests that there is a need to quantify coupled, nonlinear “mechanical dose response curves” that correlate altered stresses with cellular activity; moreover, mathematical models can help integrate such information across multiple length scales (from molecule to cell and tissue) and time scales (from minutes to days and months). For example, quantification of stress mediated synthesis and cross-linking of collagen organization within the hypertensive arterial wall, and associated signaling pathways, may suggest new therapeutic strategies based on targeted levels of inhibition.