Qin_2015_Am.J.Physiol.Heart.Circ.Physiol__ajpheart 00568 2015

We hypothesized that potentiating the bioavailability of endothelial epoxyeicosatrienoic acids (EETs) via deletion of the gene for soluble epoxide hydrolase (sEH), or downregulation of sEH expression, enhances flow/shear stress-induced dilator responses (FID) of arterioles. Using male (M) and female (F) wild type (WT) and sEH-knockout (KO) mice, isolated gracilis muscle arterioles were cannulated and pressurized at 80 mmHg. Basal tone and increases in diameter of arterioles as a function of perfusate flow (5, 10, 15, 20 and 25 microl/min) were recorded. The magnitude of FID was significantly smaller, and associated with a greater arteriolar tone in M-WT than F-WT mice, revealing a sex-difference in FID. This sex-difference was abolished by deletion of the sEH gene, as evidenced by an enhanced FID in M-KO mice to a level comparable to those observed in F-KO and F-WT mice. These three groups of mice coincidentally exhibited an increased endothelial sensitivity to shear stress (smaller WSS50) and were hypotensive. Endothelial EETs participated in the mediation of enhanced FID in M-KO, F-KO and F-WT mice, without effects on FID of M-WT mice. Protein expression of sEH was downregulated by approximately 4-fold in vessels of F-WT compared to M-WT mice, paralleled with greater vascular EET levels that were statistically comparable to those observed in both male and female sEH-KO mice. In conclusion, sex-different regulation of sHE accounts for sex differences in flow mediated dilation of microvessels in gonadally intact mice.