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.