Atheromas feel the pressure: biomechanical stress and atherosclerosis

Abstract

Atherosclerosis, a chronic vascular disease, is the underlying cause of over half the deaths in the United States each year. Variations in local vascular hemodynamics predispose select sites in the vasculature to atherosclerosis, and the atherosclerotic lesions, in turn alter the biomechanical functioning of the local microenvironment, the consequences of which are not well understood on a molecular level. Further progress in the field of atherosclerosis will require an understanding of the relationship between biomechanics, the tissue microenvironment, and the cellular and molecular response to these factors. This review summarizes this field, particularly within the context of the vascular smooth muscle cell.

Figure 1

Atherosclerotic progression is a complex process involving many cell types and the ECM. The normal human arterial intima is comprised of the endothelium, ECM (primarily collagens and elastin), and occasional VSMCs. The earliest events in atheroma formation are endothelial dysfunction and lipid accumulation in the arterial intima leading to macrophage infiltration and foam cell formation (A). Hallmarks of early lesions include migratory and proliferative VSMCs, as well (eg, integrins) as an up-regulation of cytokines and receptors that are unique to the atheroma microenvironment (B). The lesion progresses to a true atheroma and foam cells accumulate as VSMCs continue to proliferate and migrate, thereby increasing plaque size. Furthermore, VSMCs secrete collagen to generate a fibrous cap over the plaque (C, D). In advancing atherosclerosis, expansion of the plaque into the vessel lumen disrupts laminar blood flow. If the plaque is relatively VSMC-poor (due to apoptosis), especially with a lipid-rich necrotic core and thin fibrous cap, the plaque is vulnerable to fissure and rupture (C). Advanced plaques are subject to the dynamics of blood flow, from both shear and cyclic forces; as such plaques can compress during systole (C, D). However, if VSMCs are abundant within the lesion and actively secrete ECM to generate a thick fibrous cap, then the plaque will remain relatively stable, even in systole, and is unlikely to cause a clinically-recognizable event (D).

Figure 2

Biomechanic and atherosclerosis: A vicious cycle. Altered shear stress at branch point and curves is a well-known initiating step in atherosclerosis. The atherosclerotic plaque, in turn, promotes increased arterial compliance and distensibility as lipid, cells, and ECM accumulate in the vessel wall. As the vessel wall stiffens, it alters blood flow and changes the local hemodynamics. Altered stress then further promotes atherosclerosis through mechanosensing, resulting in changes in gene expression, thereby promoting increased plaque development.