Objective-Endothelium-derived vasoactive agents NO, endothelin-1 (ET-1), and prostacyclin (PGI 2 ) not only regulate vascular tone but also influence atherogenic processes, including smooth muscle migration and proliferation, as well as monocyte and platelet adhesion. Complex hemodynamics characterized by the temporal phase angle between mechanical factors circumferential strain and wall shear stress (stress phase angle [SPA]) have been implicated in regions prone to pathologic development, such as atherosclerosis and intimal hyperplasia, in coronary and peripheral arteries where the mechanical forces are highly asynchronous (SPAϭϪ180°). We determined the gene expression of endothelial NO synthase (eNOS), ET-1, and cyclooxygenase-2 (COX-2) affected by asynchronous hemodynamics (SPAϭϪ180°) relative to normal hemodynamics (SPAϭ0°) in bovine aortic endothelial cells. Methods and Results-Quantitative competitive RT-PCR analysis showed that eNOS production (at 5 and 12 hours) and COX-2 production (at 5 hours) were reduced at the gene expression level by asynchronous hemodynamics (SPAϭϪ180°) compared with synchronous hemodynamics (SPAϭ0°), whereas ET-1 exhibited an opposite trend (at 5 and 12 hours). NO, ET-1, and PGI 2 secretion followed their respective gene expression profiles after 5 and 12 hours. Conclusion-Together, these data suggest that highly asynchronous mechanical force patterns (SPAϭϪ180°) Key Words: hemodynamics Ⅲ shear stress and strain Ⅲ coronary arteries Ⅲ eNOS Ⅲ ET-1 Ⅲ COX-2 E ndothelial dysfunction is a primary event in development of atherosclerosis, vasospasm, and thrombosis. 1,2 Endothelium-derived vasoactive agents such as NO, endothelin-1 (ET-1), and prostacyclin (PGI 2 ) not only regulate vascular tone but also influence atherogenic processes, including smooth muscle migration and proliferation, as well as monocyte and platelet adhesion. 3 Endothelial cells (ECs) are a primary target for injuries such as hyperlipidemia, diabetes mellitus, and hypertension 2 but also serve as sensors and transducers of the most notable hemodynamic forces: wall shear stress (WSS) and circumferential stress that is induced by circumferential strain (CS [or stretch]). WSS and CS are widely believed to be important hemodynamic mediators of vascular regulation, atherosclerosis, and remodeling. 4 -7 Most previous studies of the role of vascular mechanical forces in atherogenesis have emphasized fluid shear stress (WSS) by itself (ie, no pressure or strain). 4 -7 A few recent studies have noted the importance of complex hemodynamics that include simultaneous flow, pressure, and diameter variation (stretch) in modulating cardiovascular function. 6 -9 Blood vessel ECs in vivo are subjected to simultaneous pulsatile CS and WSS that act approximately in perpendicular directions. The temporal phase angle between pressure and flow (impedance phase angle) generated by global wave reflection in the circulation and the local inertial effects of blood flow cause time lags to occur between CS and WSS. The temporal phase an...

The migration of vascular smooth muscle cells (SMCs) and fibroblasts into the intima after vascular injury is a central process in vascular lesion formation. The elevation of transmural interstitial flow is also observed after damage to the vascular endothelium. We have previously shown that interstitial flow upregulates matrix metalloproteinase-1 (MMP-1) expression, which in turn promotes SMC and fibroblast migration in collagen I gels. In this study, we investigated further the mechanism of flow-induced MMP-1 expression. An ERK1/2 inhibitor PD-98059 completely abolished interstitial flow-induced SMC migration and MMP-1 expression. Interstitial flow promoted ERK1/2 phosphorylation, whereas PD-98059 abolished flow-induced activation. Silencing ERK1/2 completely abolished MMP-1 expression and SMC migration. In addition, interstitial flow increased the expression of activator protein-1 transcription factors (c-Jun and c-Fos), whereas PD-98059 attenuated flow-induced expression. Knocking down c-jun completely abolished flow-induced MMP-1 expression, whereas silencing c-fos did not affect MMP-1 expression. Taken together, our data indicate that interstitial flow induces MMP-1 expression and SMC migration in collagen I gels via an ERK1/2-dependent and c-Jun-mediated mechanism and suggest that interstitial flow, ERK1/2 MAPK, c-Jun, and MMP-1 may play important roles in SMC migration and neointima formation after vascular injury.

Complex hemodynamics play a role in the localization and development of atherosclerosis. Endothelial cells (ECs) lining blood vessel walls are directly influenced by various hemodynamic forces: simultaneous wall shear stress (WSS), normal stress, and circumferential stress/strain (CS) due to pulsatile flow, pressure, and diameter changes. ECs sense and transduce these forces into biomolecular responses that may affect intercellular junctions. In this study, a hemodynamic simulator was used to investigate the combined effects of WSS and CS on EC junctions with emphasis on the stress phase angle (SPA), the temporal phase difference between WSS and CS. Regions of the circulation with highly negative SPA, such as the coronary arteries and carotid bifurcation, are more susceptible to the development of atherosclerosis. At 5 h, expression of the tight junction protein zonula occludens-1 was significantly higher for the atheroprotective SPA = 0° compared to the atherogenic SPA = −180° while the apoptosis rate was significantly higher for SPA = −180° than SPA = 0°. This decrease in tight junction protein and increase in apoptosis and associated leaky junctions suggest a decreased junctional stability and a higher paracellular permeability for atherogenic macromolecules for the atherogenic SPA = −180° compared to SPA = 0°.