Heterozygous endothelial endothelin-1 overexpression potentiates endothelium-dependent contractions in the carotid arteries of obese mice

Abstract

Elevated plasma levels of the vasoconstrictor peptide endothelin-1 (ET-1) are associated with cardiovascular risk factors such as obesity, diabetes and hypertension, in which endothelium-dependent contractions are prominent. Exogenous ET-1 promotes the release of endothelium-derived contracting factors (EDCF), but the role of endogenously produced ET-1 in these processes is unknown. Therefore, mice with tie-1 promoter driven endothelium-restricted heterozygous overexpression of ppET-1 (TET+/-) and WT littermates were kept on standard chow as lean controls or administered a high fat diet for 30 weeks to induce obesity. At sacrifice, fasting glucose levels were significantly elevated in obese animals (8.3±0.3 vs. 5.3±0.2 mmol/l in lean controls, n=6, P<0.001). Isometric tension was measured in aortic and carotid arterial rings in wire myographs. In phenylephrine-contracted aortic rings, endothelium-dependent and –independent relaxations to acetylcholine and sodium nitroprusside, respectively, were unaltered between groups. In carotid arteries, the potency of phenylephrine to evoke contractions was greater in preparations from obese TET+/- mice (pD2 6.71±0.07 vs. lean TET+/- 6.34±0.13, n=5-6, P<0.05), whereas there was no change in the contractile response to the α1-adrenergic agonist by diet-induced obesity in WT littermates. The augmented EDCF responses to acetylcholine of quiescent carotid arterial rings of obese animals were further potentiated by TET+/- (Emax 51.3±1.1% vs. 40.6±1.3% KCl in WT obese, n=6, P<0.001). The production of 6-keto PGF1α – the stable metabolite of prostacyclin – was increased significantly in preparations from obese TET+/- mice (238.4±30.0 vs. 127.0±12.7 pg/mL in obese WT littermates, n=4-6, P<0.05). In the presence of L-NAME, TP receptor activation by U46619 was more effective in obese TET+/- (Emax 151.8±5.4% vs. 126.1±4.7% KCl in WT obese, n=4-6, P<0.05). Overall, TET+/- had no effect on relaxations in obese animals, but contractile responses – EDCF-mediated ones in particular – were facilitated. The present results suggest that this is due to an increased production of vasoconstrictor prostanoids possibly combined with an augmented responsiveness of the underlying vascular smooth muscle.