Hypertension impairs cognitive function and is a leading risk factor for stroke, Alzheimer's disease and vascular dementia. Yet, the mechanisms underlying the link between cardiovascular diseases and neurovascular pathologies have not been elucidated. Using a multidisciplinary approach which includes in vitro and in vivo studies in GFAP-GCamP3 mice we propose the central hypothesis that astrocytes actively participate in cerebral autoregulation by increasing vascular tone via TRPV4 channel activation and Ca2+-dependent production of 20-HETE. Further, we hypothesize that augmented astrocyte- derived 20-HETE production in hypertension causes enhanced myogenic constriction of PA. This hypothesis predicts that cerebrovascular tone and reactivity are tightly monitored by perivascular astrocytes.
In Aim 1 we will test the hypothesis that astrocytes sense and transduce hemodynamic stimuli into specific Ca2+ response patterns via mechanosensitive TRPV4 channels.
Aim 2 will address whether hemodynamic-induced astrocytic Ca2+ responses contribute to the production of the vasoconstrictor 20-HETE, supporting increased vascular tone in PA. Finally, in Aim 3 using the ANG II model of hypertension in GPAP- GCamP3 mice we will test the hypothesis that pressure-induced increased astrocytic Ca2+, via TRPV4 channel activation, enhances 20-HETE mediated constriction of PA in hypertension. We anticipate findings from this study to move the field forwards by elucidating a novel non-vascular therapeutic target for neurovascular pathologies associated with cardiovascular diseases. This study will: 1) characterize a novel function of astrocytes in the control of vascular tone and cerebral autoregulation;2) define the cellular targets underlying myogenic- induced constriction of PA and;3) define the consequences of chronic hypertension on astrocytic-mediated alterations in vascular tone.

Public Health Relevance

Neurodegenerative and vascular disorders can lead to disruption of the neurovascular unit. In this study we will test the novel hypothesis that hemodynamic changes are sensed by perivascular astrocytes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL089067-06
Application #
8761154
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Charette, Marc F
Project Start
2007-05-01
Project End
2018-06-30
Budget Start
2014-09-02
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
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

Showing the most recent 10 out of 16 publications