Arterial Endothelial Pannexin 1 in Ischemic Stroke-Induced Vascular Dementia with Age and Sex

About This Grant

PROJECT SUMMARY/ABSTRACT Ischemic stroke is a leading cause of morbidity and mortality. Risk for ischemic stroke increases with age in both men and women, although women have a higher lifetime risk of stroke, higher rate of death due to stroke and poorer outcomes, such as worse mobility and anxiety/depression, following an ischemic stroke. Therapeutic intervention during and after ischemic stroke is currently limited to removal of the physical occlusion within the blood vessel, an intervention for which many patients do not qualify. To identify alternative novel therapeutic targets to improve ischemic stroke outcomes, we examined the role of cerebral endothelial Pannexin1 (Panx1) channels. Panx1 channels are the primary nucleotide release channels, which can regulate activation of downstream purinergic receptors and cause detrimental stroke outcomes. We previously demonstrated that deletion of endothelial Panx1 reduces cerebral artery myogenic reactivity, vasoconstriction in response to increased luminal pressure, which regulates cerebral blood flow. Deletion of endothelial Panx1 also reduced post-ischemic stroke infarct volume. Preliminary mechanistic data suggests an interaction between arterial endothelial Panx1 and αvβ3 integrins, mechanosensory proteins that may activate Panx1 channels during myogenic reactivity. Additionally, our preliminary data demonstrate an increase in Panx1 expression in cerebral endothelial cells in aged 18-month-old mice. We show that induced overexpression of endothelial Panx1 in young mice impairs cerebral blood flow recovery 24 hr post-ischemic stroke, resulting in increased infarct volume specifically in female mice. Taken together, these data suggest a detrimental role for endothelial Panx1 that contributes to poor ischemic stroke outcome, particularly in females, and may facilitate post-ischemic stroke vascular dementia. This proposal tests the hypothesis that cerebral arterial endothelial Panx1 regulates cerebral myogenic tone via interaction with integrin αvβ3, which contributes to impaired CBF recovery during ischemic stroke leading to poor stroke outcomes and cognitive impairment in aged females with the following specific aims. Aim 1 will explore the integrin αvβ3-Panx1-purinergic receptor interaction in regulation of cerebral vascular tone with age and post-ischemic stroke. In Aim 2, we will determine if ovarian estrogen is necessary for EC Panx1-dependent cerebral arterial function and chronic ischemic stroke outcome. Aim 3 will examine if arterial EC Panx1 regulates cerebral arterial function and chronic ischemic stroke outcome in a sex- or age-dependent manner. Furthermore, we will determine if post-reperfusion pharmacological inhibition of Panx1 is protective against chronic ischemic stroke outcomes in aged mice. Successful completion of our study will provide insight into the sex- and age-specific mechanistic role of Panx1 within arterial cerebral endothelial cells in the regulation of cerebral blood flow and its contribution to ischemic stroke outcome. These data may identify multiple sex- specific therapeutic targets for pharmacological intervention following an ischemic stroke leading to precision medicine strategies to improve ischemic stroke outcomes and reduce stroke-induced vascular dementia.