TRPV4 channels tune astrocytic endfoot Ca2+ to optimize neurovascular coupling

Abstract

A rise in intracellular calcium ([Ca2+]i) in astrocytes is required to communicate the energy demands of neurons to the cerebral microcirculation to precisely match local cerebral blood flow to neuronal metabolism. This “neurovascular coupling” (NVC) is essential for neuronal viability and homeostasis. A moderate rise in [Ca2+]i in the perivascular “endfoot” terminals of astrocytes in response to neuronal activation produces vasodilation of the adjacent parenchymal arteriole, whereas high endfoot [Ca2+]i can produce vasoconstriction. Thus, precise regulation of astrocytic [Ca2+]i is necessary for proper function of the cerebral microcirculation. Transient receptor potential vanilloid 4 (TRPV4) channels are Ca2+‐permeant plasma membrane cation channels that participate in intracellular Ca2+ signaling in a variety of cell types. We previously reported that both the synthetic TRPV4 agonist, GSK1016790A, and the endogenous agonist, 11,12‐EET, increase the frequency and amplitude of perivascular astrocytic endfoot Ca2+ oscillations in brain slices. Here we provide evidence from multiphoton confocal microscopy in brain slices and cerebral blood flow (CBF) measurement by laser Doppler flowmetry in vivo, that Ca2+ entry through TRPV4 in astrocytic endfeet contributes to NVC. Incubation of brain slices with the selective TRPV4 antagonist, HC‐067047 (1 μM), attenuated the parenchymal arteriolar vasodilation to neuronal stimulation by 42% (n=5). This effect was accompanied by a reduction in pre‐stimulation endfoot [Ca2+]i and in the evoked increase in endfoot [Ca2+]i in response to stimulation. Superfusion of HC‐067047 over the somatosensory cortex in mice had no effect on resting CBF, but reduced the CBF response to contralateral whisker stimulation by 9% (n=7). These results indicate that TRPV4 channels tune perivascular astrocytic enfoot [Ca2+]i to optimize NVC. This study was supported by National Heart, Lung, and Blood Institute grants HL‐44455, T32 HL‐07944, and HL‐095489.