title: Sexually dimorphic phenotype of arteriolar responsiveness to shear stress in soluble epoxide hydrolase-knockout mice.
abstract: 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. With the use of 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 μl/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 with 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 fourfold in vessels of F-WT compared with M-WT mice, paralleled with greater vascular EET levels that were statistically comparable with those observed in both male and female sEH-KO mice. In conclusion, sex-different regulation of sEH accounts for sex differences in flow-mediated dilation of microvessels in gonadally intact mice.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; Renji Hospital, Shanghai Jiaotong University School of Medicine, People's Republic of China;
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York;
authors.forename: Sharath
authors.initials: S
authors.lastname: Kandhi
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York;
authors.forename: Ghezal
authors.initials: G
authors.lastname: Froogh
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Houli
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Renji Hospital, Shanghai Jiaotong University School of Medicine, People's Republic of China; Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York;
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; an_huang@nymc.edu.
authors.forename: An
authors.initials: A
authors.lastname: Huang
mesh_terms: D000818:Animals; D001160:Arterioles / Q000201:enzymology*; D001783:Blood Flow Velocity; D001794:Blood Pressure; D015777:Eicosanoids / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000172:deficiency* / Q000235:genetics; D005260:Female; D006439:Hemodynamics; D008297:Male; D040542:Mechanotransduction, Cellular; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D012039:Regional Blood Flow; D012727:Sex Characteristics; D012737:Sex Factors; D013314:Stress, Mechanical; D013997:Time Factors; D014664:Vasodilation
chemical_list: D015777:Eicosanoids; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse
keywords: arterioles; epoxyeicosatrienoic acids; flow/shear stress-induced vasodilation; sex; soluble epoxide hydrolase