Augmented astrocyte microdomain Ca²⁺ dynamics and parenchymal arteriole tone in angiotensin II-infused hypertensive...

Hypertension is an important contributor to cognitive decline but the underlying mechanisms are unknown. Although much focus has been placed on the effect of hypertension on vascular function, less is understood of its effects on nonvascular cells. Because astrocytes and parenchymal arterioles (PA) form a functional unit (neurovascular unit), we tested the hypothesis that hypertension-induced changes in PA tone concomitantly increases astrocyte Ca²⁺ . We used cortical brain slices from 8-week-old mice to measure myogenic responses from pressurized and perfused PA. Chronic hypertension was induced in mice by 28-day angiotensin II (Ang II) infusion; PA resting tone and myogenic responses increased significantly. In addition, chronic hypertension significantly increased spontaneous Ca²⁺ events within astrocyte microdomains (MD). Similarly, a significant increase in astrocyte Ca²⁺ was observed during PA myogenic responses supporting enhanced vessel-to-astrocyte signaling. The transient potential receptor vanilloid 4 (TRPV4) channel, expressed in astrocyte processes in contact with blood vessels, namely endfeet, respond to hemodynamic stimuli such as increased pressure/flow. Supporting a role for TRPV4 channels in aberrant astrocyte Ca²⁺ dynamics in hypertension, cortical astrocytes from hypertensive mice showed augmented TRPV4 channel expression, currents and Ca²⁺ responses to the selective channel agonist GSK1016790A. In addition, pharmacological TRPV4 channel blockade or genetic deletion abrogated enhanced hypertension-induced increases in PA tone. Together, these data suggest chronic hypertension increases PA tone and Ca²⁺ events within astrocytes MD. We conclude that aberrant Ca²⁺ events in astrocyte constitute an early event toward the progression of cognitive decline.