Functional role of astrocyte glutamate receptors and carbon monoxide in cerebral vasodilation response to glutamate

Elena Parfenova, Dilyara Tcheranova, Shyamali Basuroy, Alexander L. Fedinec, Jianxiong Liu, Charles Leffler

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume302
Issue number11
DOIs
StatePublished - Jun 1 2012

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Glutamate Receptors
Carbon Monoxide
Vasodilation
Astrocytes
Glutamic Acid
N-Methylaspartate
Ionotropic Glutamate Receptors
Heme Oxygenase (Decyclizing)
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Kainic Acid Receptors
AMPA Receptors
Kainic Acid
Arterioles
Dilatation
2-Aminoadipic Acid
Swine
Gliotoxin
Heme Oxygenase-1
Hypercapnia
Nitroprusside

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Functional role of astrocyte glutamate receptors and carbon monoxide in cerebral vasodilation response to glutamate. / Parfenova, Elena; Tcheranova, Dilyara; Basuroy, Shyamali; Fedinec, Alexander L.; Liu, Jianxiong; Leffler, Charles.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 302, No. 11, 01.06.2012.

Research output: Contribution to journalArticle

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AU - Liu, Jianxiong

AU - Leffler, Charles

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