title: Astrocyte contributions to flow/pressure-evoked parenchymal arteriole vasoconstriction.
abstract: Basal and activity-dependent cerebral blood flow changes are coordinated by the action of critical processes, including cerebral autoregulation, endothelial-mediated signaling, and neurovascular coupling. The goal of our study was to determine whether astrocytes contribute to the regulation of parenchymal arteriole (PA) tone in response to hemodynamic stimuli (pressure/flow). Cortical PA vascular responses and astrocytic Ca(2+) dynamics were measured using an in vitro rat/mouse brain slice model of perfused/pressurized PAs; studies were supplemented with in vivo astrocytic Ca(2+) imaging. In vitro, astrocytes responded to PA flow/pressure increases with an increase in intracellular Ca(2+). Astrocytic Ca(2+) responses were corroborated in vivo, where acute systemic phenylephrine-induced increases in blood pressure evoked a significant increase in astrocytic Ca(2+). In vitro, flow/pressure-evoked vasoconstriction was blunted when the astrocytic syncytium was loaded with BAPTA (chelating intracellular Ca(2+)) and enhanced when high Ca(2+) or ATP were introduced to the astrocytic syncytium. Bath application of either the TRPV4 channel blocker HC067047 or purinergic receptor antagonist suramin blunted flow/pressure-evoked vasoconstriction, whereas K(+) and 20-HETE signaling blockade showed no effect. Importantly, we found TRPV4 channel expression to be restricted to astrocytes and not the endothelium of PA. We present evidence for a novel role of astrocytes in PA flow/pressure-evoked vasoconstriction. Our data suggest that astrocytic TRPV4 channels are key molecular sensors of hemodynamic stimuli and that a purinergic, glial-derived signal contributes to flow/pressure-induced adjustments in PA tone. Together our results support bidirectional signaling within the neurovascular unit and astrocytes as key modulators of PA tone.
authors.affiliation: Georgia Regents University, Augusta, Georgia 30912, and.
authors.forename: Ki Jung
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: Georgia Regents University, Augusta, Georgia 30912, and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Iddings
authors.affiliation: Georgia Regents University, Augusta, Georgia 30912, and.
authors.forename: Javier E
authors.initials: JE
authors.lastname: Stern
authors.affiliation: University of Cincinnati, Cincinnati, Ohio 45221.
authors.forename: Víctor M
authors.identifier: http://orcid.org/0000-0002-4735-0513
authors.initials: VM
authors.lastname: Blanco
authors.affiliation: Georgia Regents University, Augusta, Georgia 30912, and.
authors.forename: Deborah
authors.initials: D
authors.lastname: Croom
authors.affiliation: Georgia Regents University, Augusta, Georgia 30912, and.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Kirov
authors.affiliation: Georgia Regents University, Augusta, Georgia 30912, and jfilosa@gru.edu.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Filosa
mesh_terms: D000818:Animals; D001160:Arterioles / Q000502:physiology*; D001253:Astrocytes / Q000502:physiology*; D001921:Brain / Q000098:blood supply / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D050916:TRPV Cation Channels / Q000096:biosynthesis*; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse
keywords: astrocyte; calcium; myogenic; neurovascular; parenchymal arteriole; vascular tone