Zimmermann Ralf C, Hartman Tipton, Kavic Suzanne, Pauli Samuel A, Bohlen Peter, Sauer Mark V, Kitajewski Jan
Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
J Clin Invest. 2003 Sep;112(5):659-69. doi: 10.1172/JCI18740.
Gonadotropins induce ovarian follicle growth that is coincident with increased follicular vasculature, suggesting a role of angiogenesis in follicle development. Functional studies performed in nonhuman 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.
促性腺激素可诱导卵巢卵泡生长，这与卵泡血管生成增加同时发生，提示血管生成在卵泡发育中起作用。在非人类灵长类动物中进行的功能研究表明，给予使血管内皮生长因子（VEGF）失活的物质，经组织学分析或激素测量证实，可阻断排卵前卵泡的发育和功能。阻断VEGF受体2（VEGFR-2）的功能会改变卵泡激素分泌，提示VEGF的卵巢内效应可能由该受体介导。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，我们通过选择一种缺乏主动反馈的模型——青春期前垂体切除小鼠，来描述VEGFR-2活性在卵泡发育中的卵巢内作用。垂体切除可阻止卵泡进一步生长和成熟；然而，给予促性腺激素可刺激卵泡发育至排卵前阶段。我们报告，在存在抗血管生成剂VEGFR-2中和抗体的情况下，外源性给予的促性腺激素无法将卵泡发育驱动至排卵前阶段。这种对卵泡发育的抑制是由血管生成和卵泡腔形成的停滞引起的。我们得出结论，卵巢内VEGF/VEGFR-2途径对促性腺激素依赖性血管生成和卵泡发育至关重要。
