Astrocyte regulation of cerebral blood flow during hypoglycemia

Amy R Nippert, Pei-Pei Chiang, Armani P Del Franco, Eric A. Newman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Hypoglycemia triggers increases in cerebral blood flow (CBF), augmenting glucose supply to the brain. We have tested whether astrocytes, which can regulate vessel tone, contribute to this CBF increase. We hypothesized that hypoglycemia-induced adenosine signaling acts to increase astrocyte Ca2+ activity, which then causes the release of prostaglandins (PGs) and epoxyeicosatrienoic acids (EETs), leading to the dilation of brain arterioles and blood flow increases. We used an awake mouse model to investigate the effects of insulin-induced hypoglycemia on arterioles and astrocytes in the somatosensory cortex. During insulin-induced hypoglycemia, penetrating arterioles dilated and astrocyte Ca2+ signaling increased when blood glucose dropped below a threshold of ∼50 mg/dL. Application of the A2A adenosine receptor antagonist ZM-241385 eliminated hypoglycemia-evoked astrocyte Ca2+ increases and reduced arteriole dilations by 44% (p < 0.05). SC-560 and miconazole, which block the production of the astrocyte vasodilators PGs and EETs respectively, reduced arteriole dilations in response to hypoglycemia by 89% (p < 0.001) and 76% (p < 0.001). Hypoglycemia-induced arteriole dilations were decreased by 65% (p < 0.001) in IP3R2 knockout mice, which have reduced astrocyte Ca2+ signaling compared to wild-type. These results support the hypothesis that astrocytes contribute to hypoglycemia-induced increases in CBF by releasing vasodilators in a Ca2+-dependent manner.

Original languageEnglish (US)
Pages (from-to)1534-1546
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume42
Issue number8
DOIs
StatePublished - Aug 2022

Bibliographical note

Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported by National Institutes of Health Grants R01-EY-026514, R01-EY-026882, and P30-EY-011374 to EAN and by National Institutes of Health Grants T32 EY025187 and F31 DK116498 to ARN.

Publisher Copyright:
© The Author(s) 2022.

Keywords

  • Hypoglycemia
  • IP3R2 KO
  • adenosine
  • astrocytes
  • calcium signaling
  • cerebral blood flow

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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