Vascular Biology and Microcirculation: Mineralocorticoid receptor antagonism improves parenchymal arteriole dilation via a TRPV4-dependent mechanism and prevents cognitive dysfunction in hypertension

摘要

Hypertension and mineralocorticoid receptor activation cause cerebral parenchymal arteriole remodeling; this can limit cerebral perfusion and contribute to cognitive dysfunction. We used a mouse model of angiotensin II-induced hypertension to test the hypothesis that mineralocorticoid receptor activation impairs both transient receptor potential vanilloid (TRPV)4-mediated dilation of cerebral parenchymal arterioles and cognitive function. Mice (16−18 wk old, male, C57Bl/6) were treated with angiotensin II (800 ng·kg⁻¹·min⁻¹) with or without the mineralocorticoid receptor antagonist eplerenone (100 mg·kg⁻¹·day⁻¹) for 4 wk; sham mice served as controls. Data are presented as means ± SE; n = 5–14 mice/group. Eplerenone prevented the increased parenchymal arteriole myogenic tone and impaired carbachol-induced (10⁻⁹–10⁻⁵ mol/l) dilation observed during hypertension. The carbachol-induced dilation was endothelium-derived hyperpolarization mediated because it could not be blocked by N-nitro-l-arginine methyl ester (10⁻⁵ mol/l) and indomethacin (10⁻⁴ mol/l). We used GSK2193874 (10⁻⁷ mol/l) to confirm that in all groups this dilation was dependent on TRPV4 activation. Dilation in response to the TRPV4 agonist GSK1016790A (10⁻⁹–10⁻⁵ mol/l) was also reduced in hypertensive mice, and this defect was corrected by eplerenone. In hypertensive and eplerenone-treated animals, TRPV4 inhibition reduced myogenic tone, an effect that was not observed in arterioles from control animals. Eplerenone treatment also improved cognitive function and reduced microglia density in hypertensive mice. These data suggest that the mineralocorticoid receptor is a potential therapeutic target to improve cerebrovascular function and cognition during hypertension.>NEW & NOTEWORTHY Vascular dementia is a growing public health issue that lacks effective treatments. Transient receptor potential vanilloid (TRPV)4 channels are important regulators of parenchymal arteriole dilation, and they modulate myogenic tone. The data presented here suggest that TRPV4 channel expression is regulated by the mineralocorticoid receptor (MR). MR blockade also improves cognitive function during hypertension. MR blockade might be a potential therapeutic approach to improve cerebrovascular function and cognition in patients with hypertension.