title: Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex.
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.
authors.affiliation: 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;
authors.forename: Peter
authors.initials: P
authors.lastname: Toth
authors.affiliation: 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;
authors.forename: Stefano
authors.initials: S
authors.lastname: Tarantini
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Antonio
authors.initials: A
authors.lastname: Davila
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: M Noa
authors.initials: MN
authors.lastname: Valcarcel-Ares
authors.affiliation: 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;
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.affiliation: Biological Sciences Department, Biola University, La Mirada, California;
authors.forename: Behzad
authors.initials: B
authors.lastname: Varamini
authors.affiliation: 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;
authors.forename: Praveen
authors.initials: P
authors.lastname: Ballabh
authors.affiliation: 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.
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism and Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.affiliation: 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.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D002450:Cell Communication / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics; D006706:Homeostasis; D006940:Hyperemia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D040542:Mechanotransduction, Cellular; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D000069336:Neurovascular Coupling / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D058472:Receptors, Purinergic P2Y1 / Q000187:drug effects / Q000378:metabolism*; D013003:Somatosensory Cortex / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D014738:Vibrissae / Q000294:innervation
chemical_list: D004791:Enzyme Inhibitors; C546383:P2ry1 protein, mouse; D058912:Purinergic P2Y Receptor Agonists; D058921:Purinergic P2Y Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: astrocyte; dementia; endothelial dysfunction; endothelial nitric oxide synthase; endothelium; vascular cognitive impairment