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Am J Physiol Heart Circ Physiol. 2015 Dec 1;309(11):H1837-45. doi: 10.1152/ajpheart.00463.2015. Epub 2015 Oct 9.

Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex.

Author information

1
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Neurosurgery, University of Pecs, Pecs, Hungary; Szentagothai Research Center, Medical School, University of Pecs, Pecs, Hungary;
2
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
3
Institute for Diabetes, Obesity, and Metabolism and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
4
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
5
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Szentagothai Research Center, Medical School, University of Pecs, Pecs, Hungary;
6
Biological Sciences Department, Biola University, La Mirada, California;
7
Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York; Department of Pediatrics, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, New York Medical College, Valhalla, New York;
8
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
9
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Szentagothai Research Center, Medical School, University of Pecs, Pecs, Hungary; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
10
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Szentagothai Research Center, Medical School, University of Pecs, Pecs, Hungary; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma zoltan-ungvari@ouhsc.edu.

Abstract

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of cognitive impairment associated with aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g., hypertension, obesity). Although previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in endothelial NO synthase (eNOS), and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS(-/-)) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice, the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation-induced and ATP-mediated CBF responses, whereas, in eNOS(-/-) mice, the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio-endothelial coupling during neuronal activity, highlighting the role of ATP-mediated activation of eNOS via P2Y1 receptors in functional hyperemia.

KEYWORDS:

astrocyte; dementia; endothelial dysfunction; endothelial nitric oxide synthase; endothelium; vascular cognitive impairment

PMID:
26453330
PMCID:
PMC4698379
DOI:
10.1152/ajpheart.00463.2015
[Indexed for MEDLINE]
Free PMC Article

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