Foxc2调控Cx43增强内皮祖细胞促阴茎血管内皮损伤修复的研究

Corpora cavernosa vascular endothelium injury is an important cause of erectile dysfunction (ED). Targeted repair of penile vascular endothelium is a vital way for ED treatment. Previous studies had demonstrated that Cx43-mediated cell communication can repair damaged blood vessels by promoting the differentiation of endothelial progenitor cells (EPCs), but the effective targeting pathway of Cx43 protein regulation is still unknown. Our previous study found that Foxc2 up-regulates the expression of Cx43 in EPCs and vascular endothelial cells, and this mechanism is associated with phosphorylation of Cx43 mediated by signaling pathways. Therefore, we put forward the hypothesis that "Foxc2 can promote EPCs’ homing and differentiation by up-regulating Cx43expression, which can repair the cavernous vascular endothelium injury ". In this study, we firstly propose to explore the effect of Foxc2 on the migration, adhesion and differentiation of EPCs. Secondly, we study the mechanism of Foxc2/Cx43 for regulating the biological function of EPCs. Finally, we construct the rat model of corpora cavernosa vascular damage, and then study the homing and targeted repair effect of the Foxc2 over-expression EPCs in local damaged blood vessels after cell transplantation in the rat model, and lastly observe the penile erection improvement in the rat model with cell transplantation. This project explores the feasibility that Foxc2 can promote the repair of corpus cavernosum vascular endothelium injury by regulating Cx43 expression of EPCs, which would provide a new target for the precise treatment of vascular ED.

阴茎海绵体血管内皮损伤是勃起功能障碍(ED)的重要病因，靶向修复血管内皮是ED精准治疗的关键。既往研究证实Cx43介导的细胞通讯可促进内皮祖细胞(EPCs)分化从而修复损伤血管，但至今仍未找到靶向调控Cx43蛋白的有效方法。我们前期研究发现Foxc2可上调EPCs及血管内皮细胞Cx43的表达，并且该调控机制与Cx43磷酸化通路有关。由此我们提出“Foxc2可通过上调Cx43促进EPCs归巢与分化，靶向修复海绵体血管”这一假说。为此，本项目拟首先探索Foxc2对EPCs迁移、粘附、分化的影响；其次，研究Foxc2/Cx43调控EPCs发挥生物学功能的作用机制；最后通过在体干预海绵体动脉损伤模型，明确过表达Foxc2的EPCs在血管内皮损伤局部的靶向聚集和修复效应并最终实现阴茎勃起功能改善。本项目探索Foxc2调控Cx43促进海绵体血管内皮修复的可行性，为血管性ED的精准治疗提供新的调控靶点。

阴茎海绵体血管内皮损伤是勃起功能障碍(ED)的重要病因，靶向修复血管内皮是ED精准治疗的关键。本研究通过观察Foxc2在内皮祖细胞（EPCs）中的定位及Foxc2过表达对EPCs细胞活性的影响，研究Foxc2过表达对EPCs增殖、迁移及血管新生能力等功能的影响，并探索Foxc2介导Cx43信号通路促进EPCs增殖、迁移及血管新生的作用机制，最终验证Foxc2过表达对体内EPCs归巢及促内皮修复效应。研究发现转染Foxc2后的EPCs状态良好，定位在EPCs细胞核的Foxc2表达水平显著增加，提示高效率转染Foxc2后的EPCs凋亡不增加。过表达Foxc2的EPCs显示更强的增殖、迁移以及定向粘附功能，同时Foxc2-EPCs中Cx43mRNA表达显著升高，提示转染Foxc2后的EPCs血管细胞分化功能增强。Foxc2-EPCs注射后的糖尿病ED大鼠表现为海绵体内压显著增加，Cx43蛋白表达显著增强，提示阴茎海绵体血管功能获得改善。本研究结果为提高干细胞的治疗效果提供新思路，也开拓了Foxc2转录因子精准治疗血管性ED的临床应用前景。