Abstract P277: Mineralocorticoid Receptor Signaling Regulates TRPV4-mediated Vasodilation of Parenchymal Arterioles

Abstract

Hypertension impairs endothelium-dependent dilation of the parenchymal arterioles (PA) that regulate white matter perfusion. In the periphery, mineralocorticoid receptor (MR) activation facilitates hypertension-associated artery dysfunction; the role of MR signaling in PA dysfunction has not been defined. We hypothesized that Angiotensin II (AngII)-hypertension impairs TRPV4-mediated dilation in an MR-dependent manner. 16 week old male C57bl/6 mice were treated with AngII (800ng/kg/min) ± the MR antagonist, eplerenone (EPL; 100mg/kg/day) for 4 weeks; Sham mice served as control. PAs were isolated and studied by pressure myography. Data are presented as mean ± SEM; n=4-6 per group. AngII increased systolic blood pressure, an effect not blunted by EPL (Sham:147 ± 3; AngII: 177* ± 3; AngII+EPL: 182* ± 6mmHg; *=p<0.05 vs. Sham). However, EPL prevented the increased myogenic tone (31±1 vs 48*±4 vs 35±3 % tone; *=p<0.05 vs. Sham) and the impaired carbachol (CbCh)-induced dilation (51±3 vs 24*±2 vs 49±3 %dilation; Sham vs. AngII vs. AngII+EPL; *=p<0.05 vs. Sham) caused by AngII infusion. CbCh-induced dilation was unaltered by L-NAME (10 -5 M) and indomethacin (10 -4 M) in all groups (Sham: 51±3 vs. 53±2; AngII:24±2 vs. 28±2; AngII+EPL 49±3 vs. 47±3% dilation; CbCh vs. CbCh+L-NAME+Indomethacin) implicating endothelium-derived hyperpolarization (EDH). In contrast, the TRPV4 antagonist, GSK2193874 (GSK2, 10 -7 M) blunted the CbCh-induced dilation in all groups (Sham: 51±3 vs 13*±8; AngII: 24±2 vs 7*±2; AngII+EPL: 49±3 vs 16*±4 % dilation; CbCh vs CbCh+GSK2 ;*=p<0.05). In the AngII and AngII+EPL mice, TRPV4 inhibition reduced myogenic tone (AngII: 16±3; AngII+EPL: 17±6 %tone loss; p<0.05), an effect that was not observed in the Sham mice (2±3 %tone loss). AngII infusion decreased cerebral perfusion; EPL prevented this decrease (Sham: 938±32; AngII:596*±53; AngII+EPL:793±36 perfusion units; *=p<0.05 vs. Sham). MR activation regulates TRPV4 signaling in PAs during AngII-infusion, independent of hypertension. Impaired TRPV4 function plays a critical role in AngII-hypertension-associated changes in PA reactivity and may increase the risk of small vessel disease.