Goede V, Schmidt T, Kimmina S, Kozian D, Augustin H G
Department of Gynecology and Obstetrics, University of Göttingen Medical School, Germany.
Lab Invest. 1998 Nov;78(11):1385-94.
Cyclic angiogenic processes in the ovarian corpus luteum (CL) of monovulatory species are characterized by distinct phases of blood vessel growth, vessel maturation, and vessel regression. To characterize molecular and cellular systems that may play a role in regulating blood vessel maturation, we have (a) analyzed the spatiotemporal expression of vascular endothelial growth factor (VEGF) and its receptors VEGF-R1 (Flt-1) and VEGF-R2 (Flk-1) throughout the ovarian cycle, (b) examined the recruitment of pericytes during vessel maturation, and (c) quantitatively measured the ratio of angiopoietin-2 (Ang-2) to angiopoietin-1 (Ang-1) throughout the ovarian cycle. The data indicate that the VEGF/VEGF-receptor system is expressed not only during ovarian angiogenesis, but also with similar intensity in the nonangiogenic midstage CL. In fact, VEGF is expressed through most of the ovarian cycle, only being down-regulated during luteolysis, which leads to regression of the CL neovasculature. Pericytes are recruited soon after the induction of CL angiogenesis following the front of invading endothelial cells. Based on a double-staining immunohistochemistry technique, we developed a microvessel maturation index (MMI) that reflects the percentage of the capillary neovasculature that is associated with pericytes. The MMI in the angiogenic corpus rubrum is approximately 0.60. This value is not significantly higher in the nonangiogenic midstage CL but increases to close to 0.90 during CL regression. Lastly, an RT-PCR analysis of Ang-1 and Ang-2 expression revealed that both molecules are expressed throughout the ovarian cycle. The quantitative Ang-2/Ang-1 ratio does, however, change from 1.34 in the angiogenic CL and 1.07 in the midstage CL to 7.59 during CL regression, reflecting the strong overexpression of Ang-2 over Ang-1 during blood vessel regression. Taken together, the data support a model of a transiently maturated vasculature in the midstage CL, which is characterized by VEGF and pericyte contact-mediated endothelial cell survival and an induction of blood vessel regression during luteolysis that is characterized by the down-regulation of VEGF and the up-regulation of Ang-2.
单排卵物种卵巢黄体（CL）中的周期性血管生成过程具有血管生长、血管成熟和血管消退的不同阶段。为了表征可能在调节血管成熟中起作用的分子和细胞系统，我们进行了以下研究：（a）分析了血管内皮生长因子（VEGF）及其受体VEGF-R1（Flt-1）和VEGF-R2（Flk-1）在整个卵巢周期中的时空表达；（b）检查了血管成熟过程中周细胞的募集情况；（c）定量测量了整个卵巢周期中血管生成素-2（Ang-2）与血管生成素-1（Ang-1）的比率。数据表明，VEGF/VEGF受体系统不仅在卵巢血管生成期间表达，而且在非血管生成的中期黄体中也以相似的强度表达。事实上，VEGF在卵巢周期的大部分时间都有表达，仅在黄体溶解期间下调，这导致黄体新血管系统的消退。在CL血管生成诱导后不久，周细胞跟随侵入的内皮细胞前沿被募集。基于双染色免疫组织化学技术，我们开发了一种微血管成熟指数（MMI），该指数反映了与周细胞相关的毛细血管新血管系统的百分比。血管生成的红体中的MMI约为0.60。在非血管生成的中期黄体中，该值没有显著升高，但在黄体消退期间增加到接近0.90。最后，对Ang-1和Ang-2表达的RT-PCR分析表明，这两种分子在整个卵巢周期中均有表达。然而，定量的Ang-2/Ang-1比率确实从血管生成黄体中的1.34和中期黄体中的1.07变化到黄体消退期间的7.59，反映了血管消退期间Ang-2相对于Ang-1的强烈过表达。综上所述，数据支持中期黄体中短暂成熟的脉管系统模型，其特征是VEGF和周细胞接触介导的内皮细胞存活，以及黄体溶解期间血管消退的诱导，其特征是VEGF下调和Ang-2上调。
