Deletion of Endothelial Mineralocorticoid Receptors Confers Protection Towards Altered Vessel Contractility During Endothelial Dysfunction in Renal Vessels

Aldosterone has substantial adverse effects on cardiovascular function besides the well-known renal effects. The vascular effects of aldosterone are complex and the function of mineralocorticoid receptors (MR) expressed in endothelial cells within the renal vasculature is unknown. We hypothesized that lack MR in endothelial cells (EC) protects against endothelial dysfunction in renal vessels in a hypertensive model.
To examine the role of the MR in EC we used transgenic mice, where Cre recombinase driven by the Tie2 promoter was used to ablate the MR gene (EC-MR). EC-MR transgenics had markedly decreased MR expression in isolated aortic endothelial cells as compared to Tie2-Cre negative littermates (WT) and Tie2-Cre dependent MR excision was confirmed in renal arteries. Blood pressure, heart rate and PAH clearance were measured using indwelling catheters in conscious EC-MR mice and WT mice during AngII infusion. The role of the MR in renal EC on constriction and relaxation was investigated in the renal artery in a myograph set-up, before and after 2 or 4 weeks of AngII infusion and in perfused afferent arterioles. 24 hr urinary sodium excretion and clearance was determined by use of metabolic cages after 4 weeks of AngII infusion. Baseline as well as the rise in blood pressure and renal plasma flow following one week of AngII infusion was similar between WT and EC-MR. No differences in constriction and relaxation was observed in isolated renal arteries between groups during baseline. Decreased acetylcholine-induced relaxation was evident in both genotypes after 4 weeks of AngII infusion. However, an increased contractility was seen only in WT, but not EC-MR-/- mice. The constriction of afferent arterioles from untreated mice was not different between genotypes. No differences were found between the groups with respect to the urinary excretion and fractional excretion of sodium after 4 weeks on AngII infusion. In conclusion, EC MR does not contribute to the development of AngII induced hypertension or hypertension mediated endothelial dysfunction in renal arteries. However, the MR in EC contributes to an increased contraction of the renal artery in hypertensive mice.