Endothelial cell Pannexin1 overexpression impairs ischemic stroke outcome in a sex-dependent manner

Ischemic stroke is a leading cause of morbidity and mortality. We have previously shown that deletion of endothelial cell (EC) Panx1 reduces ischemic stroke infarct volume and reduces cerebral arterial myogenic reactivity, which regulates cerebral blood flow. We hypothesized that EC Panx1 content dictates ischemic stroke outcome and thus increased EC Panx1 expression will worsen ischemic stroke outcomes due to exacerbated myogenic tone development and impaired cerebral blood flow recovery. To test this, we generated the Cdh5-CreERT2+ ROSA26-hPanx1Tg mouse model that conditionally overexpresses the human isoform of Panx1 specifically in EC. We have found that cerebral myogenic reactivity is significantly increased with overexpression of EC Panx1 only in female mice, without alterations in peripheral vascular reactivity or blood pressure regulation. Similarly, we found that infarct size was increased and recovery of cerebral blood flow was reduced in female but not male EC Panx1 overexpressing mice. Our findings indicate a role for EC Panx1 as a mediator of ischemic stroke recovery. Furthermore, these data suggest a potential sex-dependent effect for EC Panx1, where females are more sensitive to increased EC Panx1 in cerebral vascular function and may provide a potential therapeutic target for the treatment of ischemic stroke in women.