Mineralocorticoid Receptor Signaling Regulates Parenchymal Arteriole Vasodilation and Cognitive Function

Hypertension‐associated parenchymal arteriole (PA) dysfunction reduces blood flow and impairs cognitive function. We have shown that: 1.) Transient Receptor Potential Vanilloid 4 (TRPV4) channels are important regulators of PA endothelium‐dependent dilation and 2.) mineralocorticoid receptor (MR) signaling contributes to the impaired PA endothelium‐dependent dilation in hypertension. However, if MR signaling regulates the TRPV4‐mediated dilation of PAs is less clear. We tested the hypothesis that MR activation impairs PA TRPV4‐mediated dilation in stroke‐prone spontaneously hypertensive rats (SHRSP). Pressure myography was used to assess PA endothelium‐dependent dilation from 20–22‐week‐old male normotensive Sprague Dawley (SD) rats and SHRSP ± the MR, antagonist, eplerenone (EPL; 100 mg/kg/day for 4 weeks). Data are presented as mean ± SEM; SD vs SHRSP vs SHRSP+EPL unless otherwise stated; n=4–8/group. EPL prevented the increased myogenic tone (30.1 ± 3.5 vs 47.4 ± 5.1 vs 37.0 ± 3.4% tone; p=0.02) and impaired carbachol (CCh)‐induced dilation in SHRSP (39.1 ± 4.4 vs 18.8 ± 5.1 vs 35.2 ± 5.8% dilation; p<0.0001). 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 (SD: 39.0 ± 4.4 vs 5.9 ± 4.2, SHRSP: 18.7 ± 7 vs −12.0 ± 18.7, SHRSP+EPL: 35.2 ± 5.8 vs 5.9 ± 3.6% dilation; CCh vs CCh+GSK2193874, p<0.05). Interestingly, GSK2193874 caused a loss of myogenic tone in hypertensive rats (50.8 ± 8.3 vs 22.5 ± 5.7% tone; Baseline tone vs +GSK2193874, p=0.0005), this effect was also observed in the EPL treated rats (36.1 ± 4.1 vs 19.0 ± 2.1% tone; Baseline tone vs +GSK219387, p=0.004). Removing the endothelium prevented the GSK2193874 induced loss of tone suggesting endothelial TRPV4 is important for PA myogenic tone (41.2 ± 18.1 vs 38.2 ± 19.1% tone; Baseline tone vs +GSK219387, p>0.05). Hypertension also reduced the TRPV4 mRNA expression and this was not prevented by EPL treatment (1.0 ± 0 vs 0.2 ± 0 vs 0.3 ± 0.1; p<0.0001). We confirmed these findings in a mouse model of Angiotensin II‐dependent hypertension, where we also found that EPL treatment attenuates hypertension associated cognitive dysfunction. TRPV4 −/− rats were used to assess if TRPV4 channels are important regulators of cognitive function; Wistar rats were used as control. Cognitive function was assessed using the novel object recognition test. Although there was no difference in the novel exploration coefficient between groups (0.4 ± 0.1 vs 0.3 ± 0.2; p=0.9), the TRPV4−/− rats moved significantly less (1062 ± 43 vs 526 ± 18 cm; p=0.004) and were slower (3.6 ± 0.1 vs 1.8 ± 0.3 cm/s; p=0.004) than control rats (Wistar vs TRPV4−/−). Preliminary data suggests TRPV4 deletion does not change systolic blood pressure (147 ± 0 vs 146 ± 13 mmHg). PAs from TRPV4−/− had blunted CCh‐mediated dilation (3.9% dilation, compared to approximately 40% in a control rat) and did not respond to the TRPV4 agonist, GSK1016790A. Our data suggest that MR activation regulates TRPV4 signaling in PAs. Impaired TRPV4 function plays a critical role in hypertension‐associated changes in cerebral arteriolar function and may increase the risk for the development of vascular dementia. Support or Funding Information NIH 5T32GM092715‐04 to JM Diaz‐Otero. R01HL137694 and PO1‐HL‐070687 to AM Dorrance and WF Jackson This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .