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.
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.
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