Pannexin 1 Channels in Cerebral Arterial Myogenic Regulation

University Of Virginia, Charlottesville VA

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Abstract

? DESCRIPTION (provided by applicant): The mechanism for cerebral blood flow (CBF) regulation is not currently understood. Moreover, improving CBF following an ischemic stroke continues to be an important field of study because stroke remains the fourth leading cause of death in the United States. We have recently discovered that pannexin 1 (Panx1) channels, novel ATP release channels expressed in both smooth muscle cells (SMCs) and endothelial cells (ECs), significantly contribute to the regulation of systemic arterial vascular function. In he systemic circulation, sympathetically stimulated alpha 1 adrenergic receptors activate SMC Panx1 channels to release ATP into the extracellular space, which then activates purinergic receptors to induce vasoconstriction. Unlike the systemic circulation, however, cerebral circulation is highly regulated by myogenic reactivity, an intrinsic property of SMCs that constric in response to increased luminal pressure. Recent evidence suggests purinergic receptors, which are activated by extracellular ATP, are vital for the development of myogenic tone in cerebral arteries. Recovery of CBF to ischemic regions is vital for recovery following an ischemic stroke and recent evidence suggests that cerebral arterioles have increased myogenic reactivity following middle cerebral artery occlusion (MCAO) and reperfusion in mice. Interestingly, inhibition or global deletion of Panx1 results in improved outcomes following MCAO/reperfusion in mice, although these studies were limited due to compensatory mechanisms following global deletion and non-specific inhibitors. Therefore, we hypothesize that myogenic reactivity of cerebral arteries, and thus CBF regulation, requires SMC Panx1 channel-dependent release of ATP to activate purinergic receptors and, furthermore, that Panx1 contributes to the regulation of CBF following an acute ischemia stroke and reperfusion injury. Aim 1 will measure the contribution of Panx1 in myogenic reactivity of cerebral arteries using pharmacological inhibition and inducible cell-type specific genetic deletion of Panx1. Aim 2 will characterize CBF and MCAO/reperfusion outcomes in our mice with inducible cell-type specific genetic deletion of Panx1. This project will provide novel data towards elucidating the mechanism for myogenic tone development and as well as a potential therapeutic target for improving CBF following an ischemic stroke.