慢性皮肤溃疡治疗困难，肉毒素A（BTX-A）在临床上取得良好治疗效果，然而其中分子机制尚不明确。BTX-A通过结合SV2受体而直接被神经纤维末梢内吞后抑制神经递质释放，我们发现SV2在血管内皮细胞也有表达，提示它可能直接作用于血管内皮细胞；同时BTX-A可上调血管内皮细胞VEGF表达；通过RNAseq分析发现参与血管生成的Dll4/Notch1通路相关因子表达量也升高。由于VEGF的主要受体VEGFR2可通过胞吞来激活下游信号通路，推测BTX-A可能通过直接结合血管内皮细胞SV2调节VEGFR2的内吞而促进血管生成。本项目拟：①探讨BTX-A 是否通过SV2受体直接调控内皮细胞促进血管生成；②探索BTX-A 对VEGFR2内吞及稳定性的影响；③探索BTX-A 是否通过VEGFR2激活下游Dll4/Notch1信号通路。该研究将阐明BTX-A 促进皮肤溃疡修复机制，为临床应用提供理论依据。

Treatment for chronic skin ulcers is difficult and challenging, application of botulinum toxin A (BTX-A) has achieved good clinical treatments in our hospital. The mechanism, however, is not yet clear. BXT-A taken up via SV2 by nerve terminals leads to the blockage of neurotransmitters release, we also found that SV2 is expressed in vascular endothelial cells, suggesting that BXT-A may directly act on vascular endothelial cells to promote angiogenesis. Meanwhile, BXT-A can promote the expression of VEGF and factors in Dll4/Notch1 pathway in endothelial cells. Recent evidences have demonstrated that following VEGFR2 endocytosis, the main receptor of VEGF regulating angiogenesis, downstream critical signaling can still occur in the cytoplasma. Hence, it is speculated that BTX-A may promote angiogenesis by directly binding SV2 to regulate the endocytosis of VEGFR2 in vascular endothelial cell. This project is intended to: ① determine whether BXT-A stimulates angiogenesis via SV2; ② investigate whether BXT-A A promotes VEGFR2 endocytosis and stabilizes VEGFR2 protein; ③ verify whether BXT-A activates Dll4/Notch1 signaling pathway through VEGFR2. This study will uncover the mechanism underpinning the direct effects of BXT-A on edothelial cells that promote angiogenesis, which provides theoretical basis and expands the applications of BXT-A for skin ulcers.