Preservation of endothelium-dependent relaxation in atherosclerotic mice with endothelium-restricted endothelin-1 overexpression

Muhammad Oneeb Rehman Mian, Noureddine Idris-Khodja, Melissa W. Li, Avshalom Leibowitz, Pierre Paradis, Yohann Rautureau, Ernesto L. Schiffrin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 potassiumchannels (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.

Original languageEnglish
Pages (from-to)30-37
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Oct 2013
Externally publishedYes


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