title: Female-favorable attenuation of coronary myogenic constriction via reciprocal activations of epoxyeicosatrienoic acids and nitric oxide.
abstract: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid via CYP/epoxygenases, which are catabolized by soluble epoxide hydrolase (sEH) and known to possess cardioprotective properties. To date, the role of sEH in the modulation of pressure-induced myogenic response/constriction in coronary arteries, an important regulatory mechanism in the coronary circulation, and the issue as to whether the disruption of the sEH gene affects the myogenic response sex differentially have never been addressed. To this end, experiments were conducted on male (M) and female (F) wild-type (WT) and sEH-knockout (KO) mice. Pressure-diameter relationships were assessed in isolated and cannulated coronary arteries. All vessels constricted in response to increases in intraluminal pressure from 60 to 120 mmHg. Myogenic vasoconstriction was significantly attenuated, expressed as an upward shift in the pressure-diameter curve of vessels, associated with higher cardiac EETs in M-KO, F-WT, and F-KO mice compared with M-WT controls. Blockade of EETs via exposure of vessels to 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) prevented the attenuated myogenic constriction in sEH-KO mice. In the presence of 14,15-EEZE, pressure-diameter curves of females presented an upward shift from those of males, exhibiting a sex-different phenotype. Additional administration of N(ω)-nitro-l-arginine methyl ester eliminated the sex difference in myogenic responses, leading to four overlapped pressure-diameter curves. Cardiac sEH was downregulated in F-WT compared with M-WT mice, whereas expression of endothelial nitric oxide synthase and CYP4A (20-HETE synthase) was comparable among all groups. In summary, in combination with NO, the increased EET bioavailability as a function of genetic deletion and/or downregulation of sEH accounts for the female-favorable attenuation of pressure-induced vasoconstriction.
authors.affiliation: Department of Physiology and Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Ghezal
authors.initials: G
authors.lastname: Froogh
authors.affiliation: Department of Physiology and Pharmacology, New York Medical College, Valhalla, New York; Department of Gastrointestinal Surgery of Renji Hospital, Shanghai Jiaotong University School of Medicine, People's Republic of China; and.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Physiology and Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Sharath
authors.initials: S
authors.lastname: Kandhi
authors.affiliation: Department of Physiology and Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Yicong
authors.initials: Y
authors.lastname: Le
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Houli
authors.initials: H
authors.lastname: Jiang
authors.affiliation: 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 and Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Physiology and Pharmacology, New York Medical College, Valhalla, New York; an_huang@nymc.edu.
authors.forename: An
authors.initials: A
authors.lastname: Huang
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D062186:Arterial Pressure; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000172:deficiency / Q000235:genetics; D005260:Female; D005838:Genotype; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D040542:Mechanotransduction, Cellular; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D012737:Sex Factors; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C494022:14,15-eicosa-5-enoic acid; D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D009569:Nitric Oxide; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D042926:Cytochrome P-450 CYP4A; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; D019331:NG-Nitroarginine Methyl Ester
keywords: coronary artery; myogenic response; sex; soluble epoxide hydrolase