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Roles of sex‐specific regulation of vascular soluble epoxide hydrolase in flow‐induced vasodilator responses
Author(s) -
qin jun,
Kandhi Sharath,
Froogh Ghezal,
Jiang Houli,
Sun Dong,
Huang An
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.738.2
Subject(s) - epoxide hydrolase 2 , dilator , chemistry , medicine , endocrinology , vasodilation , electrical impedance myography , basal (medicine) , vascular tone , biology , biochemistry , enzyme , insulin
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 (90–150 μm in diameter) 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 (14.9 ± 0.8 %PD at maximal flow rate), and associated with a greater arteriolar tone (61.5 ± 1.1 %PD at 80 mmHg) in M‐WT than F‐WT mice (maximal flow rate: 22.3 ± 2.1 and basal tone: 74.4 1.6 %PD), 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 expressed as smaller WSS 50 (8.9±1.3 in M‐KO; 7.9±1.0 in F‐KO and 8.7±1.1 in F‐WT) compared to M‐WT (12.4 2.0) and were hypotensive. Endothelial EETs that did not contribute to FID in M‐WT mice, participated in the mediation of enhanced FID in M‐KO, F‐KO and F‐WT mice, as evidenced by inhibiting the enhancement with PPOH (an EET synthase inhibitor). 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 comparable to those observed in both male and female sEH‐KO mice. In conclusion, sex‐different expression of sHE accounts for sex differences in FID of microvessels in gonadally intact mice, characterized as a female‐specific downregulation of sEH that imitates the action of deleting sEH gene, leading to the enhancement of FID in F‐WT mice identical to those in sEH‐KO mice. Support or Funding Information This work was supported by NIH grant HL070653