Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Division of Emergency Medicine, Department of Surgery, Duke University, Durham, North Carolina, USA.
JCI Insight. 2018 Mar 22;3(6):96272. doi: 10.1172/jci.insight.96272.
Ischemic stroke is a leading cause of morbidity and mortality in the US; however, there currently exists only one effective acute pharmacological therapeutic intervention. Purinergic signaling has been shown to regulate vascular function and pathological processes, including inflammation and arterial myogenic reactivity, and plays a role in ischemic stroke outcome. Purinergic signaling requires extracellular purines; however, the mechanism of purine release from cells is unclear. Pannexin1 (Panx1) channels are potentially novel purine release channels expressed throughout the vascular tree that couples regulated purine release with purinergic signaling. Therefore, we examined the role of smooth muscle and endothelial cell Panx1, using conditional cell type-specific transgenic mice, in cerebral ischemia/reperfusion injury outcomes. Deletion of endothelial cell Panx1, but not smooth muscle cell Panx1, significantly reduced cerebral infarct volume after ischemia/reperfusion. Infiltration of leukocytes into brain tissue and development of cerebral myogenic tone were both significantly reduced when mice lacked endothelial Panx1. Panx1 regulation of myogenic tone was unique to the cerebral circulation, as mesenteric myogenic reactivity and blood pressure were independent of endothelial Panx1. Overall, deletion of endothelial Panx1 mitigated cerebral ischemic injury by reducing inflammation and myogenic tone development, indicating that endothelial Panx1 is a possible novel target for therapeutic intervention of ischemic stroke.
缺血性脑卒中是美国发病率和死亡率的主要原因；然而，目前仅有一种有效的急性药物治疗干预措施。嘌呤能信号转导已被证明可调节血管功能和病理过程，包括炎症和动脉肌源性反应性，并在缺血性脑卒中结局中发挥作用。嘌呤能信号转导需要细胞外嘌呤；然而，细胞内嘌呤释放的机制尚不清楚。连接调节性嘌呤释放与嘌呤能信号转导的 Pannexin1 (Panx1) 通道是潜在的新型嘌呤释放通道，广泛表达于整个血管树中。因此，我们使用条件性细胞类型特异性转基因小鼠，研究了平滑肌和内皮细胞 Panx1 在脑缺血/再灌注损伤结局中的作用。内皮细胞 Panx1 的缺失而非平滑肌细胞 Panx1 的缺失显著减少了缺血/再灌注后的脑梗死体积。当小鼠缺乏内皮 Panx1 时，白细胞浸润到脑组织和脑肌源性张力的发展都显著减少。Panx1 对肌源性张力的调节是大脑循环所特有的，因为肠系膜肌源性反应性和血压不受内皮 Panx1 的影响。总体而言，内皮 Panx1 的缺失通过减少炎症和肌源性张力的发展减轻了脑缺血性损伤，表明内皮 Panx1 可能是缺血性脑卒中治疗干预的一个新靶点。
