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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Resveratrol inhibits monocyte CCR2 binding activity in an NO-, MAPK- and PI3K-dependent manner, whereas it inhibits CCR2 mRNA in an NO- and MAPK-independent, PI3K-dependent manner. These inhibitory effects of resveratrol on chemokine receptor binding and expression may contribute, in part, to its cardiovascular protective activity in vivo.

Objective-Endopeptidase )-specific peptide hydrolysis plays an important role in endothelium-mediated vasoregulation. Given the significant influence of hemodynamic forces on vascular homeostasis and pathology, we postulated that these related peptidases may be mechanosensitive. The objective of this study, therefore, was to investigate the putative role of cyclic strain in regulating the expression and enzymatic activity of EP24.15 and EP24.16 in bovine aortic endothelial cells (BAECs). Methods and Results-BAECs were cultured under conditions of defined cyclic strain (0% to 10% stretch, 60 cycles/min, 0 to 24 hours). Strain significantly increased EP24.15 and EP24.16 soluble activity in a force-and time-dependent manner, with elevations of 2.3Ϯ0.4-and 1.9Ϯ0.3-fold for EP24.15 and EP24.16, respectively, after 24 hours at 10% strain. Pharmacological agents and dominant-negative G protein mutants used to selectively disrupt Gi ␣ -and G␤␥-mediated signaling pathways attenuated strain-dependent (24 hours, 5%) increases for both enzymes. Differences in the inhibitory profile for both enzymes were also noted, with EP24.15 displaying greater sensitivity to Gi ␣2/3 inhibition and EP24.16 exhibiting greater sensitivity to Gi ␣1/2 and G␤␥ inhibition. Cyclic strain also increased levels of secreted EP24.15 and EP24.16 activity by 2.6Ϯ0.02-and 3.6Ϯ0.2-fold, respectively, in addition to mRNA levels for both enzymes (EP24.15 ϩ42%, EP24.16 ϩ56%). Key Words: metallopeptidase Ⅲ endothelial function Ⅲ cyclic strain Ⅲ G protein M echanical or hemodynamic forces associated with blood flow play an important role in the physiological control of vascular tone, remodeling, and associated pathologies. These include cyclic circumferential strain, which is caused by a transmural force acting perpendicularly to the vessel wall, and fluid shear stress, the frictional force generated as blood drags against cells. Central to the maintenance of vascular homeostasis is the endothelial cell (EC) monolayer, which constitutes a dynamic interface between the vessel wall and bloodstream, where it regulates the physiological effects of hemodynamic forces on vessel wall tone and remodeling events. These forces can modulate EC metabolism by inducing qualitative and quantitative changes in EC gene expression/posttranslational modifications, [1][2][3][4] with downstream effects on vascular cell-fate decisions (eg, migration and proliferation). Conclusions-OurVasoactive peptide hormones and their associated degradative enzymes, primarily extracellularly acting metallopeptidases, also play a crucial role in EC-mediated vasoregulation. Of particular importance are the "thermolysin-like" family of zinc metalloendopeptidases, classified by Barrett et al 5 as belonging to the Clan MA, which hydrolyze peptide bonds in substrates of fewer than 40 amino acids. Several members of this family are known to participate in the metabolism of EC-derived vasoactive peptides, and these include neutral endopeptidase (NEP; EC3.4.24.11), angiotensin-converting enzyme (ACE; E...

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