Abstract
Background: In human atherosclerosis , which is associated with elevated plasma and coronary endothelin (ET)-1 levels, ET type A receptor antagonists improved coronary endothelial function. Mice overexpressing ET-1 specifically in the endothelium (eET-1) crossed with apolipoprotein E knockout mice (Apoe-/-) exhibited exaggerated high-fat diet (HFD)-induced atherosclerosis. Since endothelial dysfunction often precedes development of atherosclerosis, we investigated whether endothelium-specific ET-1 overexpression causes endothelial dysfunction in Apoe-/- mice. Methods: Eight-week male old eET-1, Apoe-/-, eET-1/Apoe-/- and wild-type (WT) mice were fed a regular diet or HFD for 8 weeks. Endothelial function was assessed in mesenteric arteries by pressurized myography. Results: In HFD-fed mice, acetylcholine-induced endothelium-dependent relaxation (EDR) was reduced in Apoe-/- and eET-1 compared to WT (Emax: 29.2±2.9% and 51.8±7.9%, respectively, vs. 88.0±2.6%, P<0.05). Surprisingly, EDR was not impaired in eET-1/Apoe-/- (70.9±9.8%) compared to WT. Endothelium-independent relaxation to the nitric oxide (NO) donor sodium nitroprusside and contractile responses to norepinephrine were unaffected. Similar results were observed in regular diet-fed mice. In the presence of inhibitors of either NO synthase (NOS)-mediated relaxation, Nω-nitro-L-arginine methyl ester, or endothelium-dependent hyperpolarization (EDH)-mediated relaxation, apamin plus Tram34, EDR was blunted in WT (Emax: 2.8±0.4% and 35.7±8.4 respectively, P<0.01), whereas relaxation was weakly reduced or unaffected in eET-1/Apoe-/- (Emax: 68.6±9.9, P<0.05 and 80.6±8.0, respectively). However, the concomitant inhibition of NOS- and EDH-mediated relaxation strongly reduced EDR in eET-1/Apoe-/- (Emax: 43.0±8.2%, P<0.05). Conclusions: These results show an interdependence of NOS and EDH pathways in EDR in WT mice. ET-1 overexpression induced development of compensatory mechanisms in pre-atherosclerotic arteries of Apoe-/- mice, which permits either NOS or EDH pathway to mediate independently EDR. Investigation of mechanisms involved in the remodeling of EDR in eET-1/Apoe-/- mice will allow a better understanding of the ET-1 role in atherosclerosis.
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