The role of cellular adaptation to mechanical forces in atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory disease that originates at regions of arteries exposed to disturbances in fluid flow and results in progressive plaque formation in those areas. Recent work on cellular responses to flow has identified potential mechanosensors and pathways that may influence disease progression. These results led us to hypothesize that the same mechanisms that mediate adaptive responses in the vasculature become maladaptive at sites of disturbed flow. Subsequent changes in gene expression and matrix remodeling help to entrain these inflammatory pathways. These events synergize with systemic risk factors such as hyperlipidemia, smoking, and diabetes, leading to disease progression.

Figure 1. Mechanical forces on the vessel wall

(A) vessel wall with τ = shear stress parallel to vessel wall (red arrows). By contrast blood pressure (p) exerts pressure normal to vessel wall (blue arrow), which results in a circumferential stretch of the artery wall (green arrows). (B) Vascular bifurcation with disturbed flow at outer walls where atherosclerotic plaques are found. Endothelial cells align in atheroprotected but not atheroprone regions where flow is disturbed.

Figure 2. Matrix remodeling and inflammation

Sections through the carotid bifurcation stained for inflammatory markers (ICAM-1 and VCAM-1) and for fibronectin (FN). These markers are expressed only in the atheroprone region of the carotid sinus and correlate well with each other. Adapted from Orr et al, 2005, J. Cell Biol. 169:191–202.