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Query: UMLS:C0020440 (
hypercapnia
)
7,939
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Mechanosensitivity is a well-known feature of astrocytes, however, its underlying mechanisms and functional significance remain unclear. There is evidence that astrocytes are acutely sensitive to decreases in cerebral perfusion pressure and may function as intracranial baroreceptors, tuned to monitor brain blood flow. This study investigated the mechanosensory signaling in brainstem astrocytes, as these cells reside alongside the cardiovascular control circuits and mediate increases in blood pressure and heart rate induced by falls in brain perfusion. It was found that mechanical stimulation-evoked Ca
2+
responses in astrocytes of the rat brainstem were blocked by (1) antagonists of connexin channels,
connexin 43
(
Cx43
) blocking peptide Gap26, or
Cx43
gene knock-down; (2) antagonists of TRPV4 channels; (3) antagonist of P2Y
1
receptors for ATP; and (4) inhibitors of phospholipase C or IP3 receptors. Proximity ligation assay demonstrated interaction between TRPV4 and
Cx43
channels in astrocytes. Dye loading experiments showed that mechanical stimulation increased open probability of carboxyfluorescein-permeable membrane channels. These data suggest that mechanosensory Ca
2+
responses in astrocytes are mediated by interaction between TRPV4 and
Cx43
channels, leading to
Cx43
-mediated release of ATP which propagates/amplifies Ca
2+
signals via P2Y
1
receptors and Ca
2+
recruitment from the intracellular stores. In astrocyte-specific
Cx43
knock-out mice the magnitude of heart rate responses to acute increases in intracranial pressure was not affected by
Cx43
deficiency. However, these animals displayed lower heart rates at different levels of cerebral perfusion, supporting the hypothesis of connexin hemichannel-mediated release of signaling molecules by astrocytes having an excitatory action on the CNS sympathetic control circuits.
SIGNIFICANCE STATEMENT
There is evidence suggesting that astrocytes may function as intracranial baroreceptors that play an important role in the control of systemic and cerebral circulation. To function as intracranial baroreceptors, astrocytes must possess a specialized membrane mechanism that makes them exquisitely sensitive to mechanical stimuli. This study shows that opening of
connexin 43
(
Cx43
) hemichannels leading to the release of ATP is the key central event underlying mechanosensory Ca
2+
responses in astrocytes. This astroglial mechanism plays an important role in the autonomic control of heart rate. These data add to the growing body of evidence suggesting that astrocytes function as versatile surveyors of the CNS metabolic milieu, tuned to detect conditions of potential metabolic threat, such as hypoxia,
hypercapnia
, and reduced perfusion.
...
PMID:Mechanosensory Signaling in Astrocytes. 3312 90
