title: COX-2 contributes to the maintenance of flow-induced dilation in arterioles of eNOS-knockout mice.
abstract: Our previous studies demonstrated that, in gracilis muscle arterioles of male mice deficient in the gene for endothelial nitric oxide synthase (eNOS), flow-induced dilation (FID) is mediated by endothelial PGs. Thus the present study aimed to identify the specific isoform of cyclooxygenase (COX) responsible for the compensatory mediation of FID in arterioles of eNOS-knockout (KO) mice. Experiments were conducted on gracilis muscle arterioles of male eNOS-KO and wild-type (WT) mice. Basal tone and magnitude of FID of arterioles were comparable in the two strains of mice. A role for COX isoforms in the mediation of the responses was assessed by use of valeryl salicylate (3 mM) and NS-398 (10 microM), inhibitors of COX-1 and COX-2, respectively. In eNOS-KO arterioles, valeryl salicylate or NS-398 alone inhibited FID (at maximal flow rate) by approximately 51% and approximately 58%, respectively. Administration of both inhibitors eliminated the dilation. In WT arterioles, inhibition of COX-2 did not significantly affect FID, whereas inhibition of COX-1 decreased the dilation by approximately 57%. The residual portion of the response was abolished by additional administration of Nomega-nitro-L-arginine methyl ester. Western blot analysis indicated a comparable content of COX-1 protein in arterioles of WT and eNOS-KO mice. COX-2 protein, which was not detectable in arterioles of WT mice, was strongly expressed in arterioles of eNOS-KO mice, together with an upregulation of COX-2 gene expression. Immunohistochemical staining confirmed the presence of COX-2 in the endothelium of eNOS-KO arterioles. In conclusion, COX-2-derived PGs are the mediators responsible for maintenance of FID in arterioles of eNOS-deficient mice.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY 10595, USA. dong_sun@nymc.edu
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Changdong
authors.initials: C
authors.lastname: Yan
authors.forename: Azita
authors.initials: A
authors.lastname: Jacobson
authors.forename: Caroline
authors.initials: C
authors.lastname: Ojaimi
authors.forename: An
authors.initials: A
authors.lastname: Huang
authors.forename: Gabor
authors.initials: G
authors.lastname: Kaley
mesh_terms: D000818:Animals; D001160:Arterioles / Q000502:physiology*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D012459:Salicylates / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011453:Prostaglandins; D012459:Salicylates; D013449:Sulfonamides; C401835:valerylsalicylate; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D052250:Nitric Oxide Synthase Type III; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D019331:NG-Nitroarginine Methyl Ester