Kallistatin调节血管功能预防卵巢过度刺激综合征的作用及机制研究

Previous studies showed that angiogenesis and increased vascular permeability are important pathological basis of the occurrence and development of OHSS. Many groups including ours has demonstrated that Kallistatin (KS) is an endogenous anti-inflammatory and anti-angiogenesis factor, which performed its function in multiple diseases. However, the function of KS in OHSS is not yet studied. We found that KS was down-regulated under OHSS context, while the exogenous supply of KS significantly alleviated OHSS signs, including body and ovarian weight gain as well as increased vascular permeability. Thus, we speculate that KS prevents OHSS through inhibiting angiogenesis and vascular leakage. This project is to design the following contents: firstly, we will investigate the function of KS in preventing OHSS by exogenous supplying or antagonizing KS in OHSS-induced mice and KS transgenic mice; Secondly, we will elucidate the function and mechanisms of KS in inhibiting angiogenesis and vascular leakage by assessing angiogenesis and vascular permeability in animal models as well as relevant regulators. Finally, we will find out whether KS is modulated by hCG and its mechanisms. Overall, this project will clarify the function of KS in preventing OHSS and key signaling pathways, thus providing new drug candidates and intervention targets for preventing OHSS.

以往的研究表明血管过度增生及血管通透性的增加是卵巢过度刺激综合征（OHSS）发生发展的重要病理学基础。包括我们在内的研究发现Kallistatin（KS）是一种内源性的抗炎抗血管新生因子，在多种疾病中发挥功能，但其在OHSS中的作用尚待研究。预实验结果显示OHSS病理情况下KS表达下调；而外源补充KS能显著抑制小鼠出现OHSS的症状，包括体重增加、卵巢增大和血管通透性增加；由此我们的科学假设是KS通过抑制血管新生和血管通透性的增加预防OHSS的发生。本研究拟:①利用OHSS小鼠和KS转基因小鼠模型，外源补充或拮抗KS以明确其预防OHSS的作用；②检测动物模型血管新生和血管通透性情况以及相关调控因子以阐明KS抑制血管新生和血管通透性增加的作用和机制；③揭示hCG下调KS表达的作用及机制。本项目旨在明确KS预防OHSS的作用和关键信号机制，为OHSS的防治提供新的候选药物和干预靶点。

以往的研究表明血管过度增生及血管通透性的增加是卵巢过度刺激综合征（OHSS）发生发展的重要病理学基础。包括我们在内的研究发现Kallistatin是一种内源性的抗炎抗血管新生因子，在多种疾病中发挥功能，但其在OHSS中的作用尚待研究。本研究收集了临床OHSS高危患者的血液标本，并构建了OHSS的小鼠模型。我们的研究结果显示：（1）在OHSS高危患者及OHSS小鼠模型中，促OHSS发生的相关因子如VEGF、IL-6和IL-8的表达升高，而Kallistatin的表达则下降；（2）Kallistatin能够降低血管通透性的增加，可有效预防OHSS的发生且不影响小鼠排卵、妊娠及胎鼠发育; （3）Kallistatin通过Wnt/β-catenin通路下调VEGF的表达从而抑制血管内皮细胞的迁移和成管，且通过NF-kB通路下调IL-6和IL-8的表达；（4）hCG通过转录因子NR2F1下调Kallistatin的表达；（5）使用VEGF、IL-6和IL-8重组蛋白未能拮抗Kallistatin预防OHSS的作用，需要改进实验进一步研究。本研究提示Kallistatin通过Wnt/β-catenin通路和NF-kB通路调控VEGF、IL-6和IL-8的表达，进而抑制血管新生、改善血管通透性，从而预防OHSS的发生，为OHSS的预防提供了新的候选药物和干预靶点。