Engeletin protects against cerebral ischemia/reperfusion injury by modulating the VEGF/vasohibin and Ang-1/Tie-2 pathways

Engeletin is a natural derivative of Smilax glabra rhizomilax that exhibits anti-inflammatory activity and suppresses lipid peroxidation. In the present study, we sought to elucidate the mechanistic basis for the neuroprotective and pro-angiogenic activity of engeltin in a human umbilical vein endothelial cells (HUVECs) oxygen-glucose deprivation and reoxygenation (OGD/R) model system and a middle cerebral artery occlusion (MCAO) rat model of cerebral ischemia and reperfusion injury. These analyses revealed that engeletin (10, 20, or 40 mg/kg) was able to reduce the infarct volume, increase cerebral blood flow, improve neurological function, and bolster the expression of vascular endothelial growth factor (VEGF), vasohibin-2 (Vash-2), angiopoietin-1 (Ang-1), phosphorylated human angiopoietin receptor tyrosine kinase 2 (p-Tie2), and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) in MCAO rats. Similarly, engeletin (100, 200, or 400 nM) markedly enhanced the migration, tube formation, and VEGF expression of HUVECs in an OGD/R model system, while the VEGF receptor (R) inhibitor axitinib reversed the observed changes in HUVEC tube formation activity and Vash-2, VEGF, and CD31 expression. These data suggested that engeletin exhibited significant neuroprotective effects against cerebral ischemia and reperfusion injury in rats, and improved cerebrovascular angiogenesis by modulating the VEGF/vasohibin and Ang-1/Tie-2 pathways.恩格亭（Engeletin）是光叶菝葜（Smilax glabra）根茎的天然衍生物，具备抗炎活性并可抑制脂质过氧化。本研究旨在阐明恩格亭在人脐静脉内皮细胞（HUVECs）氧糖剥夺/复氧（OGD/R）模型系统，以及大脑中动脉闭塞（MCAO）大鼠脑缺血再灌注损伤模型中，发挥神经保护与促血管生成活性的分子机制。分析结果显示，恩格亭（10、20或40 mg/kg）可降低MCAO模型大鼠的脑梗死体积，增加脑血流量，改善神经功能，并上调血管内皮生长因子（VEGF）、血管抑制蛋白-2（Vash-2）、血管生成素-1（Ang-1）、磷酸化人血管生成素受体酪氨酸激酶2（p-Tie2）以及血小板内皮细胞黏附分子-1（PECAM-1/CD31）的表达水平。类似地，恩格亭（100、200或400 nM）可显著增强OGD/R模型系统中HUVECs的迁移能力与管形成能力，并上调VEGF的表达；而血管内皮生长因子受体（VEGFR）抑制剂阿昔替尼可逆转上述HUVEC管形成活性以及Vash-2、VEGF与CD31表达的变化。上述数据表明，恩格亭对大鼠脑缺血再灌注损伤具有显著的神经保护作用，并可通过调控VEGF/血管抑制蛋白通路与Ang-1/Tie-2通路改善脑血管生成。