Endothelial Mineralocorticoid Receptor Mediates Cerebrovascular Dysfunction in Parenchymal Arterioles during Angiotensin II-Hypertension

Mineralocorticoid receptor (MR) activation causes cerebral parenchymal arteriole (PA) remodeling, impaired endothelium‐dependent dilation and cognitive dysfunction in hypertension. We used a mouse model of angiotensin II (AngII)‐induced hypertension to test the hypothesis that endothelial cell mineralocorticoid receptor (EC‐MR) activation impairs parenchymal arteriole (PA) transient receptor potential vanilloid 4 (TRPV4)‐mediated dilation and cognitive function. 16–18‐week‐old MR‐intact and endothelial mineralocorticoid receptor knockout (ECMRKO) mice were treated with AngII (800ng/kg/min) for 4 weeks; shams served as controls. Data are presented as means ± SEM; n=5–14 per group. EC‐MR deletion under control conditions did result in vascular changes. EC‐MR deletion prevented the impaired PA carbachol (CCh)‐mediated dilation in hypertension but not the increased myogenic tone. The TRPV4 inhibitor, GSK2193874 (10 −7 M) was used to confirm the importance of TRPV4 activation in CCh‐mediated dilation. TRPV4 inhibition blunted the CCh‐mediated dilation in all groups. Dilation in response to the TRPV4 agonist GSK1016790A (10 −9 –10 −5 mol/L) and IK Ca /SK Ca agonist NS309 (10 −9 –10 −5 mol/L) were also reduced in the hypertensive mice and this was corrected by EC‐MR deletion. Hypertensive mice had impaired cognitive function, but this was not corrected by EC‐MR deletion. Plasma protein oxidation was not altered by EC‐MR deletion or AngII treatment. The mRNA expression of markers for neuronal support and synapse proteins, synaptophysin (SYP), brain derived neurotrophic factor (BDNF) were not altered by AngII. However, the mRNA expression of doublecortin (DC) was reduced by AngII and EC‐MR deletion prevented this. Our data shows that EC‐MR signaling mediates PA endothelium‐dependent dilation but not cognitive function and suggests that the MR is a potential therapeutic target to improve cerebrovascular function during hypertension. Support or Funding Information R01‐HL‐137694‐01 and PO1‐HL‐070687 to WF Jackson and AM Dorrance 5T32GM092715‐04 and F31NS090866 ‐ J.M. Diaz‐Otero R01‐HL095590 ‐ I.Z. Jaffe. J.M. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .