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...

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Although local wall shear stress (WSS) induced by blood flow has been implicated in atherogenesis, another prominent and often neglected hemodynamic feature, circumferential strain (CS) driven by pressure, is induced concurrently. To investigate endothelial cell (EC) responses to pathologic hemodynamics and their possible manipulation by pharmaceuticals, we simulated complete hemodynamic conditions comprised of simultaneous WSS and CS during treatment with conjugated linoleic acid (CLA), a known PPAR (-alpha and -gamma) activator and anti-atherogenic agent, on cultured EC and examined effects on gene and metabolite expression. Two hemodynamic conditions representative of distinct regions of the circulation, coronary arteries: pro-atherogenic (asynchronous WSS and CS) and straight descending aorta: non-atherogenic (synchronous WSS and CS), were applied to cultured EC during treatment with the nutraceutical CLA. Competitive-quantitative RT-PCR showed that asynchronous hemodynamics significantly reduced ( approximately 2-fold) eNOS and PPAR-gamma mRNA levels compared to synchronous hemodynamics at 5 and 12 h. ET-1 showed an opposite trend at 12 h. CLA treatment mitigated pro-atherogenic eNOS, ET-1, PPAR-alpha and -gamma mRNA expression profiles and NO and ET-1 secretion patterns during asynchronous hemodynamics. This study demonstrates the potential for a pharmacological treatment (CLA) to normalize pro-atherogenic gene expression profiles induced by hemodynamics inherent to the circulation.