Wu Lixiang, Zhang Zhenghong, Pan Xiaoyan, Wang Zhengchao
Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian 350108, P.R. China.
Department of Histology and Embryology, Jilin Medical College, Jilin, Jilin 132013, P.R. China.
Mol Med Rep. 2015 Nov;12(5):7153-9. doi: 10.3892/mmr.2015.4268. Epub 2015 Aug 28.
Vascular endothelial growth factor (VEGF) is vital in normal and abnormal angiogenesis in the ovary, particularly during the early development of the corpus luteum in the ovary. However, the molecular regulation of the expression VEGF during luteal development in vivo remains to be fully elucidated. As the expression of VEGF is mediated by hypoxia‑inducible factor (HIF)‑1α in luteal cells cultured in vitro, determined in our previous study, the present study was performed to confirm the hypothesis that HIF‑1α is induced and then regulates the expression of VEGF and VEGF‑dependent luteal development/function in vivo. This was investigated using a pregnant rat model treated with a small‑molecule inhibitor of HIF‑1α, echinomycin (Ech). The development of the corpus luteum in the pregnant rat ovary was identified via performing assays of the serum progesterone, testosterone and estradiol concentrations by radioimmunoassay, accompanied with determination of the changes in the expression levels of HIF‑1α and VEGF by reverse transcription‑quantitative polymerase chain reaction at different days of the developmental process. On day 5, serum progesterone levels were markedly increased, whereas serum levels of testosterone and estradiol did not change significantly. On day 17, the highest level of serum progesterone was observed, however, this was not the case for testosterone and estradiol. Further analysis of the expression levels of HIF‑1α and VEGF revealed that their changes were consistent with the changes in serum levels of progesterone, which occurred in the development of the corpus luteum in the ovaries of pregnant rats. Further investigation demonstrated that Ech inhibited luteal development through inhibiting the expression of VEGF, mediated by HIF‑1α, and subsequent luteal function, which was determined by detecting changes in serum progesterone on days 8 and 14. Taken together, these results demonstrated that HIF‑1α‑mediated expression of VEGF may be one of the important mechanisms regulating ovarian luteal development in mammals in vivo, which may provide novel strategies in treatment for fertility control and for certain types of ovarian dysfunction, including polycystic ovarian syndrome, ovarian hyperstimulation syndrome and ovarian neoplasia.
血管内皮生长因子（VEGF）在卵巢正常和异常血管生成中至关重要，尤其是在卵巢黄体的早期发育过程中。然而，VEGF在体内黄体发育过程中表达的分子调控仍有待充分阐明。正如我们之前研究所确定的，在体外培养的黄体细胞中，VEGF的表达由缺氧诱导因子（HIF）-1α介导，本研究旨在证实HIF-1α在体内被诱导，进而调节VEGF的表达以及VEGF依赖的黄体发育/功能这一假设。本研究使用了经HIF-1α小分子抑制剂棘霉素（Ech）处理的妊娠大鼠模型进行探究。通过放射免疫分析法检测血清孕酮、睾酮和雌二醇浓度，同时在发育过程的不同天数通过逆转录定量聚合酶链反应测定HIF-1α和VEGF表达水平的变化，以此来确定妊娠大鼠卵巢中黄体的发育情况。在第5天，血清孕酮水平显著升高，而血清睾酮和雌二醇水平无明显变化。在第17天，观察到血清孕酮水平达到最高，但睾酮和雌二醇并非如此。对HIF-1α和VEGF表达水平进一步分析发现，它们的变化与妊娠大鼠卵巢黄体发育过程中血清孕酮水平的变化一致。进一步研究表明，Ech通过抑制由HIF-1α介导的VEGF表达以及随后的黄体功能来抑制黄体发育，这是通过检测第8天和第14天血清孕酮的变化来确定的。综上所述，这些结果表明，HIF-1α介导的VEGF表达可能是体内调控哺乳动物卵巢黄体发育的重要机制之一，这可能为生育控制以及某些类型的卵巢功能障碍（包括多囊卵巢综合征、卵巢过度刺激综合征和卵巢肿瘤）的治疗提供新策略。
