Augmented astrocyte microdomain Ca2+ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

• Published in: Glia Vol. 67; no. 3; pp. 551 - 565
• Main Authors: Diaz, Juan Ramiro, Kim, Ki Jung, Brands, Michael W., Filosa, Jessica A.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.03.2019; Wiley Subscription Services, Inc
• Subjects: Angiotensin; Angiotensin II; Arterioles; Astrocytes; Blood vessels; Brain; Brain slice preparation; Calcium channels; Calcium ions; Calcium signalling; Clonal deletion; Cognitive ability; Cortex; Hemodynamics; Hypertension; Mice; myogenic tone; neurovascular unit; parenchymal arteriole; Pharmacology; Transient potential; two to five subject codes
• ISSN: 0894-1491; 1098-1136; 1098-1136
• DOI: 10.1002/glia.23564

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. Main Points Chronic hypertension (via 28‐day angiotensin II infusion) increased parenchymal arteriole tone and myogenic responses. Chronic hypertension significantly increased spontaneous and pressure‐evoked Ca2+ events within astrocyte microdomains. Ca2+ events were associated to increased transient potential receptor vanilloid 4 (TRPV4) channel, expression and activity.