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
Morrison, Helena W; Filosa, Jessica A (2016) Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice. Neuroscience 339:85-99
Filosa, J A; Morrison, H W; Iddings, J A et al. (2016) Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone. Neuroscience 323:96-109
Iddings, Jennifer A; Kim, Ki Jung; Zhou, Yiqiang et al. (2015) Enhanced parenchymal arteriole tone and astrocyte signaling protect neurovascular coupling mediated parenchymal arteriole vasodilation in the spontaneously hypertensive rat. J Cereb Blood Flow Metab 35:1127-36
Du, Wenting; Stern, Javier E; Filosa, Jessica A (2015) Neuronal-derived nitric oxide and somatodendritically released vasopressin regulate neurovascular coupling in the rat hypothalamic supraoptic nucleus. J Neurosci 35:5330-41
Kim, Ki Jung; Iddings, Jennifer A; Stern, Javier E et al. (2015) Astrocyte contributions to flow/pressure-evoked parenchymal arteriole vasoconstriction. J Neurosci 35:8245-57
Biancardi, Vinicia Campana; Son, Sook Jin; Ahmadi, Sahra et al. (2014) Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier. Hypertension 63:572-9
Lynch, Cynthia M; Kinzenbaw, Dale A; Chen, Xunxheng et al. (2013) Nox2-derived superoxide contributes to cerebral vascular dysfunction in diet-induced obesity. Stroke 44:3195-201
Filosa, Jessica A; Iddings, Jennifer A (2013) Astrocyte regulation of cerebral vascular tone. Am J Physiol Heart Circ Physiol 305:H609-19
Witthoft, Alexandra; Filosa, Jessica A; Karniadakis, George Em (2013) Potassium buffering in the neurovascular unit: models and sensitivity analysis. Biophys J 105:2046-54
Stern, J E; Filosa, J A (2013) Bidirectional neuro-glial signaling modalities in the hypothalamus: role in neurohumoral regulation. Auton Neurosci 175:51-60

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