Vascular endothelial growth factor receptor 2-mediated angiogenesis is essential for gonadotropin-dependent follicle development
Vascular endothelial growth factor receptor 2-mediated angiogenesis is essential for gonadotropin-dependent follicle development
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DOI：
10.1172/jci200318740
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发表时间：
2003-09-01
影响因子：
15.9
通讯作者：
Kitajewski, J
中科院分区：
文献类型：
--
作者：
Zimmermann, RC;Hartman, T;Kitajewski, J
促性腺激素诱导卵泡生长与卵泡血管生成增加相一致，提示血管生成在卵泡发育中起作用。在非人灵长类动物身上进行的功能研究表明，组织学分析或激素测量表明，给予使血管内皮生长因子失活的物质会阻止排卵前卵泡的发育和功能。阻断血管内皮生长因子受体2(VEGFR-2)的功能可改变卵泡激素的分泌，提示血管内皮生长因子的卵巢内效应可能是通过该受体介导的。然而，在这些先前的研究中，卵泡发育受阻的具体机制仍不清楚。在这里，我们通过选择一个缺乏主动反馈的模型-青春期前脑垂体切除的小鼠来表征卵巢内VEGFR-2活性在卵泡发育中的作用。切除垂体可以阻止晚期卵泡的生长和成熟；然而，促性腺激素可以刺激卵泡发育到排卵前阶段。我们报道，在抗血管生成药物VEGFR-2中和抗体的存在下，外源性应用促性腺激素不能将卵泡发育驱动到排卵前阶段。这种抑制卵泡发育的原因是抑制了血管生成和腔的形成。我们的结论是，卵巢内的VEGF/VEGFR-2通路在促性腺激素依赖的血管生成和卵泡发育中起关键作用。
Gonadotropins induce ovarian follicle growth that is coincident with increased follicular vasculature, suggesting a role of angiogenesis in follicle development. Functional studies performed in non-human primates show that administration of substances that inactivate VEGF block the development and function of preovulatory follicles as demonstrated by histological analysis or hormone measurements. Blockage of function of VEGF receptor 2 (VEGFR-2) alters follicular hormone secretion, suggesting that the intraovarian effect of VEGF might be mediated by this receptor. The specific mechanism by which follicular development was blocked in these previous studies remains unclear, however. Here we characterize the intraovarian role of VEGFR-2 activity on follicular development by choosing a model in which active feedback is absent, the prepuberally hypophysectomized mouse. Hypophysectomy prevents advanced follicle growth and maturation; however, follicle development to the preovulatory stage can be stimulated by administration of gonadotropins. We report that exogenously administered gonadotropins are unable to drive follicle development to the preovulatory stage in the presence of antiangiogenic agent, VEGFR-2-neutralizing Ab's. This inhibition of follicular development is caused by arrests to both angiogenesis and antrum formation. We conclude that the intraovarian VEGF/VEGFR-2 pathway is critical for gonadotropin-dependent angiogenesis and follicular development.