PI3K/AKT/Palladin介导的伪足小体形成在静脉畸形细胞外基质代谢失衡中的作用研究

Venous malformations (VM) are common vascular anomalies containing the highly dilated vessels with very few smooth muscle cells. Previous studies have demonstrated that the unstable vessels are associated with the reduced extracellular matrix (ECM) in VM. Moreover, our preliminary researches indicate the formation of podosomes in venous malformation endothelial cells (VMEC), which may play important roles in the increase of ECM degradation and result from the up-regulation of Palladin and PI3K/AKT signaling pathway in VM. The aims of our project are as follows: (1) To uncover the roles of Palladin and podosomes in the unstable vessels of VM; (2) To investigate the effects of PI3K/AKT signaling pathway in the above process; (3) To explore the feasibility of Palladin-targeting strategy to promote vascular maturation on the treatment of VM using the murine model of VM. Our project may further clarify the pathogenesis of VM, and would be beneficial for developing novel therapeutic strategies against VM.

静脉畸形是一种常见的先天性血管发育异常性疾病。现有研究及本课题组前期研究已证实细胞外基质沉积不足是导致静脉畸形中非稳态血管形成的重要因素。此外，本课题组前期实验发现：静脉畸形内皮细胞可能通过形成伪足小体，促进细胞外基质的降解，且与PI3K/AKT活化及Palladin表达上调有关。本课题旨在研究Palladin及伪足小体在静脉畸形非稳态血管形成过程中的调控作用，并深入探讨PI3K/AKT信号通路在上述过程中的介导作用和具体分子机制；在此基础上以裸鼠静脉畸形模型为实验对象，探讨靶向Palladin以促进血管稳定在静脉畸形治疗中的可行性。该项研究有可能进一步揭示静脉畸形的发病机制，并为开拓静脉畸形疾病新疗法提供理论基础。

静脉畸形是一种常见的先天性血管发育异常性疾病。现有研究及本课题组前期研究已证实细胞外基质沉积不足是导致静脉畸形中非稳态血管形成的重要因素。本项目研究发现：L914F-TIE2突变型 HUVEC明胶基质降解能力显著增强，点状、结状的伪足小体结构明显增多，主要受PI3K/AKT/Palladin信号通路调控。此外，静脉畸形中与细胞外基质相关的miR-145和miR-29b发生异常，博来霉素治疗可逆转该异常，提示miR-145和miR-29b可能是静脉畸形治疗的潜在药物靶点；静脉畸形患者外周血中细胞源性微粒浓度显著升高，局部病变抽取液中微粒浓度最高，具有显著的促凝作用，并且循环微粒中miR-29b的含量较高。