To define the vascular role of aldosterone and the mineralocorticoid receptor (MR) in cardiovascular pathophysiology, we generated a conditional transgenic mouse model that allows a spatio-temporal control of MR expression in vivo. To specifically assess the role of MR in the vessels, MR over-expression has been achieved in endothelial cells, using the tetracycline conditional system and an endothelium-specific promoter (VE-Cadherin).
We previously described increase sensitivity to vasoconstrictors (phenylephrine, endothelin-1, thromboxane-A2, angiotensin II) in mesenteric arteries such as in aorta of mice over-expressing the MR in the endothelium (MR-EC) in presence of a normal relaxation to vasodilatators (acetylcholine, bradykinin, nitroprusside). In vivo, blood pressure (BP) was increased in awaked MR-EC mice, as compared to the controls (CT) (tail-cuff method).
We have investigated, using pharmacological antagonists, the role of the small (SKCa), and the intermediate (IKCa) and the big (BKCa) conductance potassium channels in vascular function. In infra-renal aorta, endothelial SKCa and IKCa channel blockade (Apamin 1μm+TRAM-34 1μm) unmasked an impaired relaxation to acetylcholine in MR-EC mice as compared to controls. Inhibition of the smooth muscle specific BKCa channel with Iberiotoxin (0.1μm) blunted the higher phenylephrin-induced contractile response observed in MR-EC as compared to CT. Taken together, these pharmacological data suggest that endothelial MR overexpression is associated with an increased activity of EDHF-mediating endothelial Ca-activated K channels and a functional decrease of the smooth-muscle BKCa channel activity. Western-blot analyses when then performed to analyze the protein expression levels of the various channel subunits of the endothelial SK3 and IK and smooth-muscle BK channels. None of them showed significant modulation, suggesting that channel activity, rather than expression level, is affected in this model.
MR activation specifically in endothelial cells is therefore associated with increased BP and altered vascular reactivity, in absence of renal collecting duct mediated MR effects. This may be related to ion channels remodeling.Le texte complet de cet article est disponible en PDF.