Abstract W P409: Hypertension Impairs Myogenic Reactivity Without Increasing BBB Permeability of Isolated Parenchymal Arterioles: Role of TRPV4

Abstract

Introduction: Arterioles within the brain (parenchymal arterioles, PAs) are the target of hypertensive small vessel disease, and yet our understanding of how hypertension negatively impacts these vessels is limited. Hypotheses: Hypertension increases blood-brain barrier (BBB) permeability and impairs myogenic activity of PAs that leads to loss of local autoregulation of CBF and white matter lesions. We further hypothesized that inhibition of transient receptor potential vanilloid type 4 (TRPV4) channels would prevent these changes, as these channels are involved in BBB permeability and vasodilation. Methods: PAs were dissected from 18 wk female normotensive WKY (n=9) vs. hypertensive SHRSP (n=6) rats and studied isolated and pressurized in the absence or presence of the TRPV4 antagonist GSK2193874 (3 μM) intraluminally (n=6-7). PAs were perfused with 3000 MW fluorescent dextran with luminal flow (5 μl/min) and permeability assessed as the amount of dextran passing through the vessel wall at 60 mm Hg relative to a standard curve, measured using fluorescent spectroscopy. Myogenic tone was assessed by measuring changes in lumen diameter vs. pressure. The slope of the diameter vs. pressure curves was used as a measure of myogenic reactivity. Results: BBB permeability was similar between WKY vs. SHRSP (2.78 ± 0.63 vs. 2.49 ± 1.31 x10 -6 μM/mm 2 /min; p>0.05) that was unaffected by GSK219. Myogenic tone was increased in PAs from SHRSP vs. WKY (47 ± 2% vs. 36 ± 4% at 40 mm Hg; p<0.05) that was unaffected by GSK2193874 (42 ± 5% vs. 34 ± 2%; p>0.05). However, the slope of the diameter vs. pressure curves was positive and ~ 3-fold greater in SHRSP vs. WKY (m = +0.077 ± 0.064 for WKY and +0.208 ± 0.028; p=0.08), suggesting impaired autoregulation. Inhibition of TRPV4 channels improved myogenic reactivity in both WKY and SHRSP, making both slopes negative (m= -0.174 ± 0.071 for WKY;p<0.05 and -0.142 ± 0.047;p<0.01). Conclusions: These results suggest that impaired local autoregulation of PAs occurs earlier in the sequelae of chronic hypertension than an elevation of BBB permeability. In addition, TRPV4 antagonism improved myogenic reactivity, suggesting that overactivation of TRPV4 channels and vasodilation may contribute to impaired autoregulation of PAs during hypertension.