| Hemodynamic effects are an essential part of cardiovascular dynamics and biology. Physiologic mechanical factors influence vascular remodeling, homeostasis, and non-random atherosclerotic plaque localization. Endothelial cells (EC) are primary sensors and actuators of normal and pathologic hemodynamics. Recent studies have implicated the independent mechanical effects of wall shear stress (WSS) and circumferential strain (CS) as critical factors in vascular regulation and pathobiology. However, the simultaneous interaction of WSS and CS in endothelial cell vasoactive and PPAR gene expression and vasoactive metabolite production (NO, PGI2, and ET-1) has not been established. Here a hemodynamic simulator was developed for the study of physiologic interplay between WSS and CS and the consequent mechanical effects on cultured endothelial cells in vitro. It was shown that the magnitude and phase of flow (Q), pressure (P), and diameter (D) waveforms, with consequent mechanical effects on WSS and CS, can be controlled to provide a wide array of hemodynamic conditions including pro-atherogenic and normopathic states. Our studies attempt to establish a link between concurrent WSS and CS relations and pro-atherogenic vasoactive gene expression. The PPARs are nuclear transcription factors that are involved in lipid metabolism, glucose homeostasis, and vascular inflammation. PPARs are also important in atherogenesis, however there have been no studies to date that have examined the role of hemodynamics on PPAR mRNA expression response. We used an anti-atherogenic and anti-carcinogenic nutraceutical, a dietary PPAR activator called conjugated linoleic acid (CLA), in an attempt to reverse or mitigate pro-atherogenic responses to pathologic hemodynamics. CLA is a naturally occurring fatty acid found in a variety of foods such as cooked ruminant meats and dairy products.;Competitive quantitative RT-PCR was used to determine gene expression levels in endothelial cells for vasodilator genes eNOS and COX-2, vasoconstrictor gene endothelin-1 (ET-1), and transcription factor genes PPARalpha and PPARgamma. Results show that when pulsatile WSS and CS have a pro-atherogenic phase difference of -180°, eNOS, COX-2, PPARalpha, and PPARgamma decrease gene expression levels at least 2-fold at 5 hours while ET-1 increases 2-fold for -180° versus the normopathic phase angle 0° at 12 hours. We examined PPARalpha and PPARgamma gene expression under normal and atherogenic hemodynamics. CLA was used during pro-atherogenic hemodynamics and showed a reduction in the negative EC mRNA and metabolite responses. PPARalpha, PPARgamma, and eNOS mRNA expression increased under normal and pathologic hemodynamics with CLA treatment with respect to controls. The atheroprotective metabolite production of nitric oxide was augmented 2-fold under CLA and hemodynamic treatment while endothelin-1 production decreased.;In conclusion, the phase difference between WSS and CS can induce pathological or normal mRNA and metabolite responses in ECs and CLA can mitigate negative pro-atherogenic responses to pathologic hemodynamics. |
