转录因子FOXA2调控血管内皮细胞间质转化过程的机制研究

Endothelial-mesenchymal transition（EndMT）contribute to the regulation of endothelial function, the structural remodeling of myocardium, blood vessel and valve. It also plays a key role in the occurrence and development of cardiovascular diseases, but the underlying mechanism is seldom known. It is well known that many genes significantly change in their gene expression during EndMT. Our preliminary data have first confirmed that transcription factor FOXA2, which binds to the promoter of VE-cadherin directly, is one of the key factors preventing EndMT of vascular endothelial cells. In this proposal, we will continue to focus on the regulatory functions of FOXA2 on gene expression during EndMT. We intend to study the function of FOXA2 in the TGF-β-induced EndMT of human umbilical vein endothelial cells(HUVEC). We plan to study the mechanism of FOXA2 mediates the stimulation of End-type genes. This hypothesis will be further tested in the EndMT of vascular endothelial cells in spontaneously hypertensive rats (SHR). We hope that this study will present a new rationale for developing more effective and better therapies for vascular endothelial cell injury, and provide scientific basis for early diagnosis in the clinical practice.

内皮间质转化（EndMT）能够调节血管内皮功能，在心肌、血管、瓣膜等病理重构过程中发挥关键作用，直接影响心脏肾脏纤维化、高血压等疾病的进程，但其具体机制尚不明确。基因表达调控在这一过程中具有决定性作用。在我们的前期工作中首次发现，转录因子FOXA2结合在内皮标志基因VE-cadherin的启动子上，并可以抑制血管内皮细胞EndMT过程。根据前期实验结果，我们推测FOXA2通过直接调控VE-cadherin的转录水平从而抑制EndMT过程。以此为基础，本项目以FOXA2为研究对象，在TGF-β诱导的人脐静脉内皮细胞(HUVEC)体外细胞模型中，系统阐述EndMT过程中FOXA2的具体作用，探讨血管内皮细胞中FOXA2刺激内皮型基因表达的分子机制，并在自发性高血压大鼠模型的血管内皮细胞EndMT过程中验证上述调控机制。研究结果有助于揭示血管内皮细胞的损伤机制，为临床早期诊治提供科学依据。

血管内皮细胞稳态失衡所致血管内皮细胞损伤是心血管疾病的起始步骤，高血压、高糖、高脂、衰老等都会影响血管内皮稳态并造成血管损伤。我们聚焦在局部恶劣环境对血管内皮细胞造成损伤过程及其相关机制探索，从临床样本、动物整体模型、细胞分子水平等多层面、系统深入地研究其机制，发现：1). 转录因子FOXA2直接调控内皮型特异基因VE-cadherin和间质型特异基因Snail，抑制血管内皮细胞EndMT过程，维持血管内皮特性，抵抗血管损伤； 2). 在高同型半胱氨酸血症的临床样本和动物模型中，NRP1-p38 MAPK通路激活HMGB1表达促进血管局部损伤；3). 在糖尿病肾病动物模型和患者样本中，PKM2通过非典型作用激活STAT3/NF-kB通路，促进免疫炎症反应并导致损伤加重；4). 通过相关文献整理分析发现，高密度脂蛋白（HDL）介导的胆固醇流出能力降低导致心血管疾病概率上升。通过本项目的实施和探索，为血管内皮稳态失衡和损伤修复提供了新的理论依据和潜在干预靶点。