The main focus of this study is to characterize the cellular mechanisms underlying functional hyperemia in the cerebral cortex. Functional hyperemia occus as a function of the communication between neurons, astrocytes and the cerebral microcirculation. Disturbances in the signaling pathways leading to the proper hyperemic response have been linked to a number of pathologies including hypertension, stroke, migraine, and spreading depression, to mention a few. Although functional hyperemia occurs within seconds, the underlying mechanisms mediating such rapid signaling response are still to be defined. This project will address three major aims: First, to determine if astrocytes are intermediaries in neurovascular coupling (Aim 1). Second, to determine if the mechanism by which astrocytes communicate with parenchymal arterioles, to induce vasodilation, results from the rapid activation of Ca2+-activated K+ (BK) channels and the release of K+ into the narrow space between the astrocytic endfoot and vascular cells. Also to determine if epoxyeicosatrienoic acids contribute to the activation of BK channels in the astrocytic endfeet amplifying the signaling communication between astrocytes and blood vessels (Aim 2). Third, to determine if both functional and structural alterations occur in the neurovascular unit during hypertension (Aim 3). We hypothesize that following neuronal stimulation, the rise in intracellular Ca2+ in the astrocytes activated BK channels in astrocytic endfeet resulting in the rapid release of K+ (a strong vasodilator) in the space between the endfoot and the vascular cells. The rise in Ca2+ also increases the production of epoxyeicosatrienoic acids which act on BK channels in the astrocytic endfeet further activating these channels. Because functional and anatomical changes in neurons, asttrocytes and parenchymal arterioles are linked to one another, an understanding of the modes of communication within the neural-glial-vascular network under physiological conditions will provide insights on pathologies, such as hypertension, which affect one or more of these three cellular components constituting the neurovascular unit.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089067-05
Application #
8059688
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (92))
Program Officer
Charette, Marc F
Project Start
2007-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$294,000
Indirect Cost
$94,000
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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