title: Preservation of endothelium-dependent relaxation in atherosclerotic mice with endothelium-restricted endothelin-1 overexpression.
abstract: In human atherosclerosis, which is associated with elevated plasma and coronary endothelin (ET)-1 levels, ETA receptor antagonists improve coronary endothelial function. Mice overexpressing ET-1 specifically in the endothelium (eET-1) crossed with atherosclerosis-prone apolipoprotein E knockout mice (Apoe(-/-)) exhibit exaggerated high-fat diet (HFD)-induced atherosclerosis. Since endothelial dysfunction often precedes atherosclerosis development, we hypothesized that mice overexpressing endothelial ET-1 on a genetic background deficient in apolipoprotein E (eET-1/Apoe(-/-)) would have severe endothelial dysfunction. To test this hypothesis, we investigated endothelium-dependent relaxation (EDR) to acetylcholine in eET-1/Apoe(-/-) mice. EDR in mesenteric resistance arteries from 8- and 16-week-old mice fed a normal diet or HFD was improved in eET-1/Apoe(-/-) compared with Apoe(-/-) mice. Nitric oxide synthase (NOS) inhibition abolished EDR in Apoe(-/-). EDR in eET-1/Apoe(-/-) mice was resistant to NOS inhibition irrespective of age or diet. Inhibition of cyclooxygenase, the cytochrome P450 pathway, and endothelium-dependent hyperpolarization (EDH) resulted in little or no inhibition of EDR in eET-1/Apoe(-/-) compared with wild-type (WT) mice. In eET-1/Apoe(-/-) mice, blocking of EDH or soluble guanylate cyclase (sGC), in addition to NOS inhibition, decreased EDR by 36 and 30%, respectively. The activation of 4-aminopyridine-sensitive voltage-dependent potassium channels (Kv) during EDR was increased in eET-1/Apoe(-/-) compared with WT mice. We conclude that increasing eET-1 in mice that develop atherosclerosis results in decreased mutual dependence of endothelial signaling pathways responsible for EDR, and that NOS-independent activation of sGC and increased activation of Kv are responsible for enhanced EDR in this model of atherosclerosis associated with elevated endothelial and circulating ET-1.
authors.affiliation: Lady Davis Institute for Medical Research (M.O.R.M., N.I.-K., M.W.L., A.L., P.P., Y.R., E.L.S.), and Department of Medicine (E.L.S.), Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Muhammad Oneeb Rehman
authors.initials: MO
authors.lastname: Mian
authors.forename: Noureddine
authors.initials: N
authors.lastname: Idris-Khodja
authors.forename: Melissa W
authors.initials: MW
authors.lastname: Li
authors.forename: Avshalom
authors.initials: A
authors.lastname: Leibowitz
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Yohann
authors.initials: Y
authors.lastname: Rautureau
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D012720:Severity of Illness Index; D014664:Vasodilation / Q000235:genetics
chemical_list: D019332:Endothelin-1