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.
Footnotes
- Received May 21, 2013.
- Accepted July 30, 2013.
This work was supported by the Canadian Institutes of Health Research (CIHR) [Grant 37917], a Canada Research Chair (CRC) on Hypertension and Vascular Research from the CIHR/Government of Canada CRC program; and by the Canada Fund for Innovation [Grant 202891] (all to E.L.S.).
M.O.R.M. and N.I.-K. contributed equally to this work.
Parts of this work were previously presented as an oral presentation at the following meetings: Rautureau Y, Li MW, Leibowitz A, Paradis P, and Schiffrin EL (2010) Remodeling of endothelial function in atherosclerotic mice overexpressing endothelial endothelin-1, in Scientific Sessions 2010 of the Council for High Blood Pressure Research of the American Heart Association; 2010 Oct 13–16; Washington, DC; and Li MW, Ebrahimian T, Paradis P, Schiffrin EL (2009) Effect of endothelin-1 overexpression on vascular structure and function of apolipoprotein E knockout mice, in The 11th International Conference on Endothelin; 2009 Sept 9–12; Montréal, QC, Canada.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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