蛋白激酶CK2调节内皮祖细胞参与子宫内膜异位病灶血管发生的机制研究

Neovascularization plays a central role in the development of endometriosis. Scientists demonstrated that mobilization and recruitment of endothelial progenitor cells are regulated by angiogenic growth factors and associated signal pathway, through which they act as an important role in lesion vasculogenesis. In addition, we already found that protein kinase CK2 inhibitor effectively inhibited the forming of new blood vessels and growth of endometriotic lesions. However, the mechanism of CK2 regulating endothelial progenitor cells involved in vasculogenesis of endometriotic lesions is still not clear. Therefore, we will focus on this important pathophysiological mechanism and use dorsal skinfold chamber model, which takes the most powerful advantage in the research of neovascularization, to make a further study that protein kinase CK2 promotes VEGF, FGF-2 and concerning important factors such as HIF-1α\SDF-1\CXCR4 expression to regulate endothelial progenitor mobilization and recruitment to vasculogenesis in endometriotic lesions, through which the inhibition of vasculogenesis supplies a novel treatment strategy for endometriosis.

新生血管在子宫内膜异位症发生发展中起着至关重要的作用。研究表明内皮祖细胞通过血管生成因子及其重要信号通路实现其动员和募集参与到新生血管的发生发展中。申请人前期研究表明蛋白激酶CK2抑制剂能有效抑制子宫内膜异位病灶新生血管形成和病灶生长，而CK2对内皮祖细胞参与子宫内膜异位病灶血管发生的调节机制尚不清楚。因此，我们拟以子宫内膜异位症血管发生为研究对象，采用申请人最熟练掌握的实验动物模型（Doral Skinfold Chamber Model拥有新生血管研究不可替代的优势），深入研究蛋白激酶CK2促进血管生成因子VEGF，FGF-2生成及重要通路相关因子HIF-1α\SDF-1\CXCR4上调，进而导致内皮祖细胞动员、募集的机制，为临床抑制新生血管治疗子宫内膜异位症提供新的策略。

新生血管在子宫内膜异位症发生发展中起着至关重要的作用。研究表明内皮祖细胞通过血管生成因子及其重要信号通路实现其动员和募集参与到新生血管的发生发展中.本项研究主要证明蛋白激酶CK2抑制剂能有效抑制雌激素诱导的子宫内膜异位病灶新生血管形成和病灶生长，并提出并证明了CK2对内皮祖细胞参与子宫内膜异位病灶血管发生的机制，蛋白激酶CK2以依赖于sdf -1- cxcr4的方式，通过基质细胞参与雌激素介导的内皮祖细胞向子宫内膜异位症病变的归巢。经稳定转染蛋白激酶CK2载体(HESC-CK2)或雌激素预处理的子宫内膜基质细胞的条件培养基(CM)可显著增强EPCs的迁移和募集。相比之下，使用CK2选择性抑制剂CX-4945处理的HESCs的CM，抑制了EPCs的流动性和生存能力。此外，CK2过表达可通过激活AKT/mTOR通路显著上调子宫内膜基质细胞源性因子1 (SDF-1)的表达和分泌。使用SDF-1受体cxcr4特异性抑制剂AMD3100治疗完全逆转了ck2增强的EPCs迁移。此外，我们拟以子宫内膜异位症血管发生为研究对象，建立BALB/c小鼠内异症模型，使用了实验动物模型（Doral Skinfold Chamber Model拥有新生血管研究不可替代的优势），在体内模型中验证蛋白激酶CK2对子宫建立同种异体移植 Dorsal Skinfold Chamber 小鼠子宫内膜异位症模型的促进作用，为临床抑制新生血管治疗子宫内膜异位症提供新的策略。