title: Purinergic signaling triggers endfoot high-amplitude Ca2+ signals and causes inversion of neurovascular coupling after subarachnoid hemorrhage.
abstract: Neurovascular coupling supports brain metabolism by matching focal increases in neuronal activity with local arteriolar dilation. Previously, we demonstrated that an emergence of spontaneous endfoot high-amplitude Ca2+signals (eHACSs) caused a pathologic shift in neurovascular coupling from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage model animals. Extracellular purine nucleotides (e.g., ATP) can trigger astrocyte Ca2+oscillations and may be elevated following subarachnoid hemorrhage. Here, the role of purinergic signaling in subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling was examined by imaging parenchymal arteriolar diameter and astrocyte Ca2+signals in rat brain slices using two-photon fluorescent and infrared-differential interference contrast microscopy. We report that broad-spectrum inhibition of purinergic (P2) receptors using suramin blocked eHACSs and restored vasodilatory neurovascular coupling after subarachnoid hemorrhage. Importantly, eHACSs were also abolished using a cocktail of inhibitors targeting Gq-coupled P2Y receptors. Further, activation of P2Y receptors in brain slices from un-operated animals triggered high-amplitude Ca2+events resembling eHACSs and disrupted neurovascular coupling. Neither tetrodotoxin nor bafilomycin A1 affected eHACSs suggesting that purine nucleotides are not released by ongoing neurotransmission and/or vesicular release after subarachnoid hemorrhage. These results indicate that purinergic signaling via P2Y receptors contributes to subarachnoid hemorrhage-induced eHACSs and inversion of neurovascular coupling.
authors.affiliation: Department of Pharmacology, University of Vermont, Burlington, VT, USA.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Pappas
authors.affiliation: Department of Pharmacology, University of Vermont, Burlington, VT, USA.
authors.forename: Masayo
authors.initials: M
authors.lastname: Koide
authors.affiliation: Department of Pharmacology, University of Vermont, Burlington, VT, USA George.Wellman@uvm.edu.|Department of Surgery, Division of Neurosurgery, University of Vermont, Burlington, VT, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Wellman
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D008297:Male; D008833:Microcirculation / Q000502:physiology; D036641:Microscopy, Fluorescence, Multiphoton; D000069336:Neurovascular Coupling / Q000502:physiology*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D058470:Receptors, Purinergic P2Y / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013345:Subarachnoid Hemorrhage / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013498:Suramin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D058921:Purinergic P2Y Receptor Antagonists; D058470:Receptors, Purinergic P2Y; D013498:Suramin
keywords: Subarachnoid hemorrhage; astrocyte Ca2+ signaling; astrocyte endfeet; neurovascular coupling; purinergic receptors