Obesity and heterozygous endothelial overexpression of prepro-endothelin-1 modulate responsiveness of mouse main and segmental renal arteries to vasoconstrictor agents

AIMS: Levels of the endothelium-derived peptide endothelin-1 (ET-1) are elevated in obese humans, and ET-1 mediated vascular tone is increased. Renal arterial smooth muscle is highly responsive to ET-1. Whether or not endothelium-derived ET-1 affects contractions of the renal artery under normal conditions or in obesity is unknown. The present study was designed to investigate whether or not overexpression of endogenous ET-1 in the endothelium affects the responsiveness of the main and segmental renal arteries differently in obesity. MAIN METHODS: Mice with tie-1 promoter-driven endothelium-restricted heterozygous overexpression of preproendothelin-1 were used (TET(het)). Obesity was induced in TET(het) mice and wild-type (WT) littermates by feeding a high fat diet for 30 weeks; lean controls were kept on standard chow. The renal arteries were studied in wire myographs testing contractions (in the presence of l-NAME) to ET-1, serotonin, and U46619. KEY FINDINGS: Contractions to ET-1 were comparable between groups in main renal arteries, but augmented in segmental preparations from obese mice. Serotonin-induced responses were enhanced in obese TET(het) mice renal arteries compared to lean controls. Concentration-contraction curves to U46619 were shifted significantly to the left in main renal arteries of obese animals, and the maximal response was significantly increased between lean and obese TET(het) mice. SIGNIFICANCE: These results indicate an augmented responsiveness of main renal arteries in obesity particularly to TP receptor activation. When combined with endothelial ET-1 overexpression this effect is even more pronounced, which may help to gain further insights into the mechanisms of hypertension in obesity.