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Role of cerebrovascular endothelial dysfunction and oxidative/nitrative stress in impaired functional hyperemia: implications for age‐related vascular cognitive impairment
Author(s) -
Tarantini Stefano,
Toth Peter Joseph,
Davila Antonio,
ValcarcelAres Marta Noa,
Tucsek Zsuzsanna,
Varamini Behzad,
Ballabh Praveen,
Sonntag William E,
Baur Joseph A,
Csiszar Anna,
Ungvari Zoltan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.953.1
Subject(s) - purinergic receptor , medicine , enos , endothelial dysfunction , endocrinology , oxidative stress , reactive hyperemia , vasodilation , adenosine , nitric oxide , nitric oxide synthase
Previous studies demonstrate that aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g. hypertension, obesity) promote cerebrovascular dysfunction by decreasing bioavailability of NO and increasing production of O 2 . − and reactive nitrogen species. 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 the aforementioned conditions and previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions. Despite these advances, 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 eNOS and the role of P2Y 1 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, mimicking oxidative/nitrative stress‐mediated impairment of functional hyperemia and microvascular endothelial responses observed in aged mice. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice the selective and potent P2Y 1 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 P2Y 1 receptors in functional hyperemia. Support or Funding Information This work was supported by grants from the American Heart Association, the National Center for Complementary and Alternative Medicine, and the National Institute on Aging