Asynchronous Shear Stress and Circumferential Strain Reduces Endothelial NO Synthase and Cyclooxygenase-2 but Induces Endothelin-1 Gene Expression in Endothelial Cells

Abstract

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...

Collecting Duct-Derived Endothelin Regulates Arterial Pressure and Na Excretion via Nitric Oxide

“…How perfusion pressure increases CD ET-1 production is speculative, although one possibility is tubule flow rate; shear stress increases endothelial cell ET-1 production. 25,26 Two other aspects of the pressure-excretion studies deserve comment. First, the BP difference between CD ET-1 KO and control mice was abolished by isoflurane anesthesia.…”

Nitric oxide and coronary vascular endothelium adaptations in hypertension

“…2,5,6 The coronary artery is characterized by asynchronous hemodynamics, wherein the wall shear stress from blood flow is out of phase with the circumferential strain from blood pressure 105 and this may play a role in determining the heterogeneous eNOS expression in the coronary arterial tree. 106,107 Further support for the role of hemodynamics in eNOS protein expression comes from studies in miniature swine following prolonged aerobic exercise training. 108 Following weeks of training, eNOS protein content was increased by over 50% in coronary arteries and small and large arterioles, but unaltered in coronary conduit and intermediate arterioles, 108 suggesting that steady state adaptations to exercise hemodynamic stimuli include nonuniform changes in eNOS expression that lead to an NO-mediated improvement in coronary resistance artery endothelium-dependent dilation.…”

Cell adhesion molecule mediation of myocardial inflammatory responses associated with ventricular pacing

“…It has been shown that endothelial CAM expression can be modulated by mechanical stimuli, which is recognized through stress-sensitive promoter elements (13). Hemodynamic forces, such as fluid shear stress, are known to regulate vascular wall structure/function including EC cell shape, nitric oxide and prostacyclin production, EC proliferation, and CAM expression (2,3,7,20). Studies have demonstrated that exposure of EC to normal laminar flow patterns produces low levels of CAM and enhances the production of antiadhesive factors (17,20).…”

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