title: Functional role of astrocyte glutamate receptors and carbon monoxide in cerebral vasodilation response to glutamate.
abstract: In newborn pigs, vasodilation of pial arterioles in response to glutamate is mediated via carbon monoxide (CO), a gaseous messenger endogenously produced from heme degradation by a heme oxygenase (HO)-catalyzed reaction. We addressed the hypothesis that ionotropic glutamate receptors (iGluRs), including N-methyl-D-aspartic acid (NMDA)- and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA)/kainate-type receptors, expressed in cortical astrocytes mediate glutamate-induced astrocyte HO activation that leads to cerebral vasodilation. Acute vasoactive effects of topical iGluR agonists were determined by intravital microscopy using closed cranial windows in anesthetized newborn pigs. iGluR agonists, including NMDA, (±)1-aminocyclopentane-cis-1,3-dicarboxylic acid (cis-ACPD), AMPA, and kainate, produced pial arteriolar dilation. Topical L-2-aminoadipic acid, a gliotoxin that selectively disrupts glia limitans, reduced vasodilation caused by iGluR agonists, but not by hypercapnia, bradykinin, or sodium nitroprusside. In freshly isolated and cultured cortical astrocytes constitutively expressing HO-2, iGluR agonists NMDA, cis-ACPD, AMPA, and kainate rapidly increased CO production two- to threefold. Astrocytes overexpressing inducible HO-1 had high baseline CO but were less sensitive to glutamate stimulation of CO production when compared with HO-2-expressing astrocytes. Glutamate-induced astrocyte HO-2-mediated CO production was inhibited by either the NMDA receptor antagonist (R)-3C4HPG or the AMPA/kainate receptor antagonist DNQX. Accordingly, either antagonist abolished pial arteriolar dilation in response to glutamate, NMDA, and AMPA, indicating functional interaction among various subtypes of astrocytic iGluRs in response to glutamate stimulation. Overall, these data indicate that the astrocyte component of the neurovascular unit is responsible for the vasodilation response of pial arterioles to topically applied glutamate via iGluRs that are functionally linked to activation of constitutive HO in newborn piglets.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, 38163, USA. hparfeno@uthsc.edu
authors.forename: Helena
authors.initials: H
authors.lastname: Parfenova
authors.forename: Dilyara
authors.initials: D
authors.lastname: Tcheranova
authors.forename: Shyamali
authors.initials: S
authors.lastname: Basuroy
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Fedinec
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Liu
authors.forename: Charles W
authors.initials: CW
authors.lastname: Leffler
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001160:Arterioles / Q000187:drug effects* / Q000502:physiology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002248:Carbon Monoxide / Q000378:metabolism*; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005260:Female; D005971:Glutamates / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D016202:N-Methylaspartate / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D005971:Glutamates; D017470:Receptors, Glutamate; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D007608:Kainic Acid