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1 Physiology, New York Medical College, Valhalla, New York, United States
2 Pathology, Xuzhou Medical College, Xuzhou, Jiangsu, China
* To whom correspondence should be addressed. E-mail: dong_sun{at}nymc.edu.
Our previous studies demonstrated that in gracilis muscle arterioles of male mice deficient in the gene for eNOS, flow-induced dilation (FID) is mediated by endothelial prostaglandins. 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 using valeryl salicylate (3 mM) and NS-398 (10 µM), 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 ~51 and ~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 ~57%. The residual portion of the response was abolished by additional administration of L-NAME. 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 those 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 prostaglandins are the mediators responsible for the maintenance of FID in arterioles of eNOS deficient mice.
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