PEDF降低血管通透性阻碍卵巢过度刺激综合征发生发展的作用及机制研究

Ovarian Hyper-stimulation Syndrome is a potentially life-threatening complication of assisted reproduction, characterised by hyper-vasopermeability, with the effect and mechanism of anti-angiogenic factor in OHSS were largely unknown. Pigment epithelium-derived factor (PEDF) is a highly potent physiological anti-angiogenic factor regulated by sex hormones, known to play an indirect suppression role of anti-vasopermeability property in retina and kidney through inhibition of VEGF. However, our results shown that PEDF may exert a direct inhibitory effect on vasopermeability through regulating VE-cadherin/β-catenin complex which was an important component of cell junction. Wnt/β-catenin signal pathway was quite important in the process of cardiovascular development, and its abnormally activation caused ectopic deposition of β-catenin so as to impair cell junction, and increased the vasopermeability. Therefore, we deduced that the decreased PEDF in OHSS is working through activating Wnt/β-catenin to relocating VE-cadherin/β-catenin, the cell junction complex so as to increase vasopermeability and take part in the occurrence and development of OHSS.

卵巢过度刺激综合征（OHSS）是危及生命的辅助生殖并发症，毛细血管通透性的增加是其主要特征，关于血管通透抑制因子在OHSS的发生发展中的作用尚不清楚。色素上皮衍生因子（PEDF）是一种受性激素调控的重要的血管新生抑制因子，以往的研究认为PEDF能够通过拮抗血管内皮生长因子（VEGF）发挥间接抑制视网膜和肾脏血管通透性的作用，但我们的预实验结果表明PEDF能够促进内皮细胞间黏附连接重要复合物VE-cadherin/β-catenin的胞膜定位发挥直接抑制血管通透性的作用。Wnt/β-catenin信号通路在心血管发育过程中发挥重要的作用，预实验结果表明其异常激活能够引起β-catenin异位沉积损害细胞连接，因此我们推断OHSS中低表达的PEDF可能通过激活Wnt/β-catenin信号通路抑制细胞连接复合物VE-cadherin/β-catenin从而增加血管通透性，促进OHSSS的发生。

卵巢过度刺激综合征（OHSS）是医源性疾病，随着辅助生殖技术日益普及，逐渐受到重视。OHSS患者由血管通透性增加引起的体液大量渗出可能危及患者性命。PEDF是影响血管通透性的重要分子，但其在OHSS中的相关作用及其机制研究较少，因此本研究重在探索PEDF在OHSS患者中的表达情况及其可能影响血管通透性的机制。首先动物实验和临床标本都表明，血清PEDF水平在OHSS中都是显著降低的。运用实验室构建的重组质粒纯化一批PEDF重组蛋白，并在动物水平补充重组PEDF蛋白能够部分纠正OHSS小鼠血管通透性以及由此引起的体重和卵巢重量的增加。此外在机制方面，细胞WB和动物卵巢组织IHC都表明OHSS中降低的PEDF有可能是通过下调VE-cadherin/β-catenin复合物水平影响血管内皮细胞紧密连接，从而增加血管通透性，参与OHSS发生发展的。本研究拓宽了PEDF参与生理病理改变的范围，也为OHSS可能机制的研究提供了更多依据。