Notch1/DLL4信号通路在子宫内膜异位症血管生成中的作用及其机制

Endometriosis is a leading cause of infertility with the ascending tendency in recent years, because of its complex pathogenesis, usually poor efficacy. Angiogenesis is essential for the initiation, growth, invasion, and recurrence of endometriosis. The vascular endothelial growth factor (VEGF) and Notch/Dll4 signaling pathways have been identified as critical in the regulation of embryonic vascular development. In our previous study, we detected the expression of Notch1, Dll4 and VEGF molecules in the endometriosis lesion, VEGF is a key regulator in angiogenesis. The researches on key science problems are: What roles do the Notch1/Dll4 pathway take in angiogenesis of endometriosis? What is the molecular mechanism? Is the Notch/Dll4 signaling pathway highly interacted with the VEGF signaling pathway? The present study was therefore designed to approach clinical pathological characteristics of angiogenesis in endometriosis, mechanism research in cell model, evaluation and therapeutic effect in animal model of nude mice with endometriosis by molecular biology et al.. To discuss the possibility of medicine intervention by Notch1/Dll4 signaling pathway for endometriosis. Through studying the mechanisms of angiogenesis, we may identify that the Notch/Dll4 pathway activated by VEGF initiate a novel signaling cross-talk between endometriosis and endothelial cells that promoted angiogenesis. We may find ways to control the angiogenesis process in endometriosis as novel approaches to endometriosis treatment.

子宫内膜异位症是导致继发性不孕的常见原因，且发病呈逐年上升趋势，目前尚无有效治疗方式。血管生成是异位内膜侵袭种植的关键环节，但其机制尚不明确。Notch信号通路在调控血管发育中具有关键作用。我们前期研究发现内异症病灶中Notch1、Dll4及VEGF呈现高表达，VEGF是已知促进血管生成的重要调控因子，因此，我们提出关键科学问题：内异症病灶中Notch1/Dll4信号通路对血管生成有何作用？分子机制如何？是否与VEGF信号通路存在交互作用？对此，本课题拟从内异症临床标本血管生成特征-体外细胞模型机制研究-裸鼠探索治疗模型三个不同的层面，运用分子生物学等方法，阐明Notch1/Dll4信号通路在子宫内膜异位症血管生成中起重要作用，与VEGF信号通路共同作用于内异症病灶的血管生成。探讨通过Notch信号通路干预内异症发生的可能性，进一步完善内异症血管生成的分子机制，为其治疗提供新靶点奠定基础。

子宫内膜异位症（简称内异症，Endometriosis，EMs）是指具有活性的子宫内膜种植并生长在子宫腔以外所引起的一种病变。在育龄妇女的发病率约6%~10%，占继发性不孕妇女的50%，占妇科住院患者的30%~40%，占慢性盆腔疼痛患者的66%。它的典型症状包括不孕、痛经和慢性盆腔疼痛等症状，困扰处于人生黄金时期的这部分女性。血管生成(angiogenesis)是指血管内皮细胞在原有血管的基础上经一系列血管新生因子的相互调控发生增殖、迁移以及重塑，最终形成新生血管的过程。异位内膜的侵袭种植是一个多因素参与的病理生理过程，主要包括3个阶段，即：黏附、侵袭及血管生成。因此，寻找阻断新生血管形成的治疗靶点有助于为EMs的治疗提供新的思路。本项目聚焦子宫内膜异位症病灶微环境变化对病灶内血管生成影响的作用机制，从临床发现问题，建立整体离体模型，从分子水平研究子宫内膜异位症病灶微环境中炎症小体激活释放促进血管生成的机制以及Notch1信号通路与血管新生的关系，从临床到转基因动物再回到细胞水平有层次系统地进一步理解微环境中炎症小体的变化对子宫内膜异位症发生发展影响的机制，为阐明子宫内膜异位症血管生成与微环境中炎症小体变化的联系及其可能的影响机制提供理论依据，为EMs的治疗提供新的思路。