The Regulation of Vascular Endothelial Growth Factor by Hypoxia and Prostaglandin F2α during Human Endometrial Repair
The Regulation of Vascular Endothelial Growth Factor by Hypoxia and Prostaglandin F2α during Human Endometrial Repair
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DOI：
10.1210/jc.2010-2971
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发表时间：
2011-08-01
影响因子：
5.8
通讯作者：
Critchley, Hilary O. D.
中科院分区：
文献类型：
--
作者：
Maybin, Jacqueline A.;Hirani, Nikhil;Critchley, Hilary O. D.
背景：人类子宫内膜在月经后具有非凡的重复修复能力，但其调节作用仍不明确。孕激素水平下降，前列腺素（PG）F-2 α合成增加，导致螺旋小动脉收缩。我们假设，孕酮撤退，PGF（2 α），和缺氧增加血管内皮生长因子（VEGF），子宫内膜修复factor.Design和结果：收集子宫内膜活检（n = 47）与伦理批准和同意。RT-PCR检测VEGF mRNA表达水平在月经期明显升高（P < 0.01）。VEGF蛋白在增生期子宫内膜组织中的分泌量最高。用100 nM PGF（2 α）或缺氧（0.5%O-2）处理子宫内膜上皮细胞系和原代人子宫内膜基质细胞，导致VEGF mRNA和蛋白质显著增加。PGF（2 α）与缺氧同时作用时，VEGF表达最高（P < 0.05-0.001）。联合用药组分泌期子宫内膜组织中VEGF表达也明显增加（P < 0.05）。然而，在用PGF（2 α）和/或缺氧处理时，增殖期外植体显示VEGF没有增加。暴露于孕激素和其撤出在体外，但只有在缺氧和PG. Hypoxia-inducible因子-1 α（HIF-1 α）沉默与RNA干扰抑制缺氧诱导的VEGF表达在子宫内膜细胞，但没有改变PGF（2 α）诱导的VEGF expression.Conclusions：子宫内膜VEGF增加的时候，子宫内膜修复。预后撤退，PGF（2 α），缺氧是必要的，这种围绝经期VEGF的表达。缺氧通过HIF-1 α增加VEGF，而PGF（2 α）以HIF-1 α非依赖性方式起作用。因此，在子宫内膜修复过程中，有两种途径调节VEGF的表达。（临床内分泌代谢杂志96：2475-2483，2011）
Context: The human endometrium has an exceptional capacity for repeated repair after menses, but its regulation remains undefined. Premenstrually, progesterone levels fall and prostaglandin (PG) F-2 alpha synthesis increases, causing spiral arteriole constriction. We hypothesized that progesterone withdrawal, PGF(2 alpha), and hypoxia increase vascular endothelial growth factor (VEGF), an endometrial repair factor.Design and Results: Endometrial biopsies were collected (n = 47) with ethical approval and consent. VEGF mRNA, quantified by quantitative RT-PCR, was increased during menstruation (P < 0.01). VEGF protein was maximally secreted from proliferative endometrial explants. Treatment of an endometrial epithelial cell line and primary human endometrial stromal cells with 100 nM PGF(2 alpha) or hypoxia (0.5% O-2) resulted in significant increases in VEGF mRNA and protein. VEGF was maximal when cells were cotreated with PGF(2 alpha) and hypoxia simultaneously (P < 0.05-0.001). Secretory-phase endometrial explants also showed an increase in VEGF with cotreatment (P < 0.05). However, proliferative-phase explants showed no increase in VEGF on treatment with PGF(2 alpha) and/or hypoxia. Proliferative tissue was induced to increase VEGF mRNA expression when exposed to progesterone and its withdrawal in vitro but only in the presence of hypoxia and PG. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) silencing with RNA interference suppressed hypoxia-induced VEGF expression in endometrial cells but did not alter PGF(2 alpha)-induced VEGF expression.Conclusions: Endometrial VEGF is increased at the time of endometrial repair. Progesterone withdrawal, PGF(2 alpha), and hypoxia are necessary for this perimenstrual VEGF expression. Hypoxia acts via HIF-1 alpha to increase VEGF, whereas PGF(2 alpha) acts in a HIF-1 alpha-independent manner. Hence, two pathways regulate the expression of VEGF during endometrial repair. (J Clin Endocrinol Metab 96: 2475-2483, 2011)