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

Abstract

Hypertension and mineralocorticoid receptor activation cause cerebral parenchymal arteriole remodeling; this can limit cerebral perfusion and contribute to cognitive dysfunction. We utilized a mouse model of angiotensin II-induced hypertension to test the hypothesis that mineralocorticoid receptor activation impairs both TRPV4-mediated dilation of cerebral parenchymal arterioles and cognitive function. 16-18-week-old male C57bl/6 mice were treated with angiotensin II (800ng/kg/min) ± the mineralocorticoid receptor antagonist, eplerenone (100mg/kg/day) for 4 weeks; sham mice served as controls. Data are presented as mean ± SEM; n=5-14 per group. Eplerenone prevented the increased parenchymal arteriole myogenic tone and impaired carbachol-induced (10-10mol/L) dilation observed during hypertension. The carbachol-induced dilation was endothelium-derived hyperpolarization mediated because it could not be blocked by L-NAME (10mol/L) and indomethacin (10mol/L). We used GSK2193874 (10mol/L) to confirm that in all groups this dilation was dependent on TRPV4 activation. Dilation in response to the TRPV4 agonist GSK1016790A (10-10mol/L) was also reduced in the hypertensive mice and this defect was corrected by eplerenone. In the 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 the hypertensive mice. These data suggest that the mineralocorticoid receptor is a potential therapeutic target to improve cerebrovascular function and cognition during hypertension.

Transient receptor potential vanilloid 4 channels are important regulators of parenchymal arteriole dilation and cognitive function

“…TRPV4 channel deletion did not change the generation of myogenic tone but resulted in a severe impairment in PA dilation suggesting a critical role for this channel in cerebral arteriolar dilation. This is consistent with previous studies in TRPV4 −/− mice and with our previous studies in C57BL/6 mice where inhibition of TRPV4 channels with the pharmacological antagonist GSK2193874 severely blunted PA dilation . Studies in the Nelson laboratory also showed that AngII hypertension alters the coupling of TRPV4 channels to the anchoring protein AKAP‐150 and that this impairs the channel activity and endothelium‐dependent dilation in mesenteric arteries .…”

“…That study suggests that TRPV4 channels play a minor role in L‐NAME– but not in AngII‐induced hypertension. However, TRPV4 channels play an important role in endothelial dysfunction in AngII hypertension …”

“…The altered cognition could be associated with changes in the expression of neuronal markers such as synaptophysin, a marker for neuronal function and synaptic plasticity, and doublecortin, a marker for new and immature neurons . Recent studies show reduced mRNA expression of these markers in AngII‐hypertensive mice with cognitive impairment . Studies in old rats also show a correlation between reduction in synaptophysin levels and the degree of dementia development .…”

“…We have previously shown that aging is associated with remodeling of PAs . Also, that hypertension causes inward hypotrophic remodeling and impairs endothelium‐dependent dilation of PAs; these changes were associated with reduced cerebral perfusion and impaired cognitive function …”

“…In endothelial cells, TRPV4 channel activation allows for Ca 2+ influx that activates intermediate and small conductance Ca 2+ ‐activated potassium channels (IK Ca and SK Ca ) to elicit endothelium‐derived hyperpolarization (EDH) dilation in peripheral arteries and large pial cerebral arteries . TPRV4 channels are critical regulators of PA endothelium‐dependent dilation in normotensive and hypertensive rats and mice . AngII‐hypertensive mice have impaired TRPV4‐mediated dilation and cognition, and treatments that improve TRPV4‐mediated dilation also correct the cognitive dysfunction .…”