Greb R R, Heikinheimo O, Williams R F, Hodgen G D, Goodman A L
The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk 23507, USA.
Hum Reprod. 1997 Jun;12(6):1280-92. doi: 10.1093/humrep/12.6.1280.
We investigated hormonal regulation of endometrial angiogenesis in menstruating primates. This study was designed to demonstrate: (i) that cell-specific vascular endothelial growth factor (VEGF) production and expression in monkey endometrium are regulated by steroid receptor ligands; and (ii) mifepristone (RU 486) alters VEGF production even in the absence of a progestin agonist. Endometrial VEGF production was compared by computer-assisted immunohistochemical analysis during induced hypoestrogenism and after oestradiol, progestin, or antiprogestin (mifepristone) treatment. VEGF gene expression was estimated by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in endometrial samples from castrate cynomolgus monkeys, from intact monkeys in the luteal phase, and from monkeys treated for 20 days with levonorgestrel (LNG) or mifepristone. VEGF staining intensities in glandular epithelium and VEGF mRNA expression were highest in hypoestrogenic monkeys. Progestin treatment induced intense VEGF staining in the stroma. Gene expression of VEGF-189, but not other isoforms, was higher in progesterone- and progestin (LNG)-exposed endometria compared to mifepristone-exposed endometria or endometria from anovulatory cycles (P < 0.04). Mifepristone abolished VEGF staining in glandular epithelium almost completely. We conclude that VEGF protein and VEGF mRNA expression levels in primate endometrium depend on the steroidal milieu. Anti-angiogenic effects of mifepristone via suppression of VEGF production might represent a mechanism for its quelling effects on endometrium.
我们研究了月经周期灵长类动物子宫内膜血管生成的激素调节机制。本研究旨在证明：（i）猴子宫内膜中细胞特异性血管内皮生长因子（VEGF）的产生和表达受类固醇受体配体调控；（ii）即使在没有孕激素激动剂的情况下，米非司酮（RU 486）也会改变VEGF的产生。通过计算机辅助免疫组织化学分析比较了诱导性低雌激素状态下以及雌二醇、孕激素或抗孕激素（米非司酮）治疗后子宫内膜VEGF的产生情况。通过定量逆转录聚合酶链反应（RT-PCR）估计了去势食蟹猴、黄体期完整猴以及用左炔诺孕酮（LNG）或米非司酮治疗20天的猴子宫内膜样本中VEGF基因的表达。低雌激素状态的猴腺上皮中的VEGF染色强度和VEGF mRNA表达最高。孕激素治疗可诱导基质中出现强烈的VEGF染色。与米非司酮处理的子宫内膜或无排卵周期的子宫内膜相比，孕激素和孕激素（LNG）处理的子宫内膜中VEGF - 189的基因表达更高（P < 0.04），而其他异构体则不然。米非司酮几乎完全消除了腺上皮中的VEGF染色。我们得出结论，灵长类动物子宫内膜中VEGF蛋白和VEGF mRNA的表达水平取决于甾体环境。米非司酮通过抑制VEGF产生的抗血管生成作用可能是其对子宫内膜产生抑制作用的一种机制。
