This is a proposal to investigate the function and regulation of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis in the vasculature, more specifically, its participation in endothelium dysfunction inmodels of increased vascular expression of cytochrome P450 (CYP) 4A. 20-HETE is a primaryeicosanoid in the microcirculation where it participates in the regulation of vascular tone. In rat renalarteries, CYP4A expression and 20-HETE production increased with decreased arterial diameter.CYP4A overexpression in small arteries and arterioles increased vascular reactivity and myogenic tone.Recent studies and preliminary results suggest that the endothelium is a target for 20-HETE bioactions.Smooth muscle-specific CYP4A1 expression via Ad-SM22-4A1 induces a marked CYP4A-dependentand 20-HETE-mediated endothelial sprouting in renal arterial microvessels. In vitro, 20-HETE is apotent angiogenic factor stimulating capillary-like tube formation of endothelial cells by a mechanismthat may include MAPK activation and induction of inflammatory and angiogenic proteins (IL-8 andVEGF). In vivo, intravenous injection of Adv-CYP4A2 causes hypertension and renal arteries fromthese rats display endothelial dysfunction, which can be reversed by inhibition of CYP4A activity.Arteries from Adv-CYP4A2-transduced rats produce more 20-HETE and less NO; they also expresshigher levels of inflammatory proteins (ICAM and VCAM). These findings raise the possibility thatvascular 20-HETE is an important determinant of endothelial dysfunction, a condition that ischaracterized by decreased NO bioavailability and enhanced endothelial activation, and are the basisfor the proposal's hypothesis: Vascular overexpression of CYP4A fosters prohypertensivemechanisms via increased production of 20-HETE in a manner that may include endothelialdysfunction and activation. This hypothesis will be tested by 1) determining the relationship betweenhypertension, endothelial dysfunction and activation, CYP4A expression and 20-HETE synthesis; 2)determining whether the functional consequences of increased vascular expression of CYP4A isassociated with endothelial expression and synthesis of CYP4A and 20-HETE, respectively; and 3)exploring mechanisms underlying 20-HETE mediated endothelial dysfunction and activation.
Showing the most recent 10 out of 468 publications
