Astrocytes regulation of vascular tone: role in hypertension

DESCRIPTION (provided by applicant): 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.