Abstract：
The pericytes (PCs) surrounding capillaries are vital regulators of capillary constriction. Persistent PC contraction results in the increased capillary constriction, therefore leading to the impaired cerebral blood flow (CBF) recovery after reperfusion and worsening the clinical outcomes in stroke patients. However, the potential determinants of PC functions during ischemia/reperfusion are poorly understood. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit Delta (PIK3CD/PI3Kδ) is a crucial factor involved with neuronflammation during ischemic stroke. PI3Kδ has shown the expression in PCs, while its effect on PC functions has not been explored yet. In this study, a rodent ischemia/reperfusion model was established in C57BL/6 mice via transient middle cerebral artery occlusion and reperfusion (MCAO/R). The PI3Kδ expression in ischemic penumbra was remarkably upregulated following MCAO/R induction. PI3Kδ inhibitor CAL-101 improved the CBF recovery, ischemic brain injury, and suppressed capillary constriction in MCAO/R mice. Besides, the production of tumor necrosis factor alpha (TNF-α), an inducer for tissue injury, and the expression of transient receptor potential vanilloid type 2 (TRPV2), a channel protein permitting calcium (Ca2+) uptake, were significantly reduced in ischemic penumbra after CAL-101 treatment. In vitro, oxygen-glucose deprivation and reoxygenation (OGD/R) enhanced the expression of PI3Kδ and TRPV2 in primary mouse PCs. CAL-101 suppressed the TNF-α-induced TRPV2 expression in OGD/R-treated PCs, thus inhibiting the Ca2+ uptake and PC contraction. Collectively, this study suggests that PI3Kδ is a critical regulator of PC function during ischemic stroke.
摘要：
毛细血管周围的周细胞（PC）是毛细血管收缩的重要调节剂。持续的PC收缩导致毛细血管收缩增加，因此，导致再灌注后脑血流（CBF）恢复受损，并恶化卒中患者的临床结局。然而,对缺血/再灌注期间PC功能的潜在决定因素了解甚少。磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基Delta（PIK3CD/PI3Kδ）是缺血性中风中涉及神经元炎症的关键因素。PI3Kδ已在PC中显示表达，虽然它对PC功能的影响尚未被探索。在这项研究中,通过短暂的大脑中动脉闭塞再灌注（MCAO/R）在C57BL/6小鼠中建立了啮齿动物缺血/再灌注模型。MCAO/R诱导后，缺血半影中的PI3Kδ表达显着上调。PI3Kδ抑制剂CAL-101提高了CBF的回收率，缺血性脑损伤，并抑制MCAO/R小鼠的毛细血管收缩。此外,肿瘤坏死因子α（TNF-α）的产生，组织损伤的诱导物,和瞬时受体电位香草素2型（TRPV2）的表达，允许钙（Ca2+）摄取的通道蛋白，在CAL-101治疗后，缺血半暗带显着降低。体外，氧糖剥夺和复氧（OGD/R）增强了原代小鼠PC中PI3Kδ和TRPV2的表达。CAL-101在OGD/R处理的PCs中抑制TNF-α诱导的TRPV2表达,从而抑制Ca2+的摄取和PC的收缩。总的来说，这项研究表明，PI3Kδ是缺血性卒中期间PC功能的关键调节因子。
