Cummins PM, von Offenberg Sweeney N, Killeen MT, Birney YA, Redmond EM, Cahill PA. Cyclic strain-mediated matrix metalloproteinase regulation within the vascular endothelium: a force to be reckoned with. Am J Physiol Heart Circ Physiol 292: H28 -H42, 2007. First published September 1, 2006; doi:10.1152/ajpheart.00304.2006.-The vascular endothelium is a dynamic cellular interface between the vessel wall and the bloodstream, where it regulates the physiological effects of humoral and biomechanical stimuli on vessel tone and remodeling. With respect to the latter hemodynamic stimulus, the endothelium is chronically exposed to mechanical forces in the form of cyclic circumferential strain, resulting from the pulsatile nature of blood flow, and shear stress. Both forces can profoundly modulate endothelial cell (EC) metabolism and function and, under normal physiological conditions, impart an atheroprotective effect that disfavors pathological remodeling of the vessel wall. Moreover, disruption of normal hemodynamic loading can be either causative of or contributory to vascular diseases such as atherosclerosis. EC-matrix interactions are a critical determinant of how the vascular endothelium responds to these forces and unquestionably utilizes matrix metalloproteinases (MMPs), enzymes capable of degrading basement membrane and interstitial matrix molecules, to facilitate force-mediated changes in vascular cell fate. In view of the growing importance of blood flow patterns and mechanotransduction to vascular health and pathophysiology, and considering the potential value of MMPs as therapeutic targets, a timely review of our collective understanding of MMP mechanoregulation and its impact on the vascular endothelium is warranted. More specifically, this review primarily summarizes our current knowledge of how cyclic strain regulates MMP expression and activation within the vascular endothelium and subsequently endeavors to address the direct and indirect consequences of this on vascular EC fate. Possible relevance of these phenomena to vascular endothelial dysfunction and pathological remodeling are also addressed. endothelial cells; smooth muscle; shear stress MECHANICAL OR HEMODYNAMIC forces associated with blood flow play a pivotal role in the physiological control of vascular tone, remodeling, and the initiation and progression of vascular pathologies. Disruption of normal hemodynamic loading can be either causative of or contributory to several life-threatening diseases including hypertension (HT), intimal hyperplasia (IH), and atherosclerosis. With respect to the latter, for example, a variety of systemic risk factors (e.g., smoking, hyperlipidemia, genetic factors) have been found to promote atherosclerosis. Although these factors affect blood vessels equally, atherosclerotic lesions typically develop at predictable locations (e.g., branch points, bifurcations, sites of injury and infection), suggesting that the development of clinically significant plaques involves a complex interplay between vascular anatomy,...

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