Loss of parenchymal arteriolar dilation to K+ contributes to impaired neurovascular coupling in chronic angiotensin II hypertension

Abstract

Hypertension has catastrophic effects on the brain. Hypertension induced by angiotensin II (Ang II) impairs neurovascular coupling (NVC), the process by which vasodilation accompanies increases in neuronal activity, but the mechanisms of this dysfunction are not clear. A rise in Ca2+ concentration in perivascular astrocytic processes (“endfeet”) that surround brain parenchymal arterioles (PAs) is a critical step in NVC by stimulating vasodilator release. One key mediator released by endfeet during NVC is K+, which activates inward rectifier K+ channels (Kir) on smooth muscle cells (SMCs) producing vasodilation. We investigated endfoot Ca2+ dynamics and K+‐mediated vasodilation in chronic Ang II hypertension. Using multiphoton microscopy, we found that endfoot Ca2+ dynamics were not altered in brain slices from Ang II hypertensive mice, yet the vasodilation to neuronal depolarization was reduced by 54%. Correspondingly, dilation to K+ was essentially absent in pressurized PAs from hypertensive mice. Further, Kir current in hypertensive pial artery SMCs was reduced from 7 pA/pF to <1 pA/pF. Our results indicate that chronic Ang II‐dependent hypertension profoundly impairs Kir function in brain arterial SMCs, resulting in loss of K+‐mediated dilation and dysfunctional NVC. This study was supported by NIH grants P01 HL095488, R01 HL44455, R01 HL098243, T32 HL07944, and the Totman Medical Research Trust.