Halder J B, Zhao X, Soker S, Paria B C, Klagsbrun M, Das S K, Dey S K
Department of Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, Kansas 66160-7338, USA.
Genesis. 2000 Mar;26(3):213-24.
The mechanism(s) by which localized vascular permeability and angiogenesis occur at the sites of implantation is not clearly understood. Vascular endothelial growth factor (VEGF) is a key regulator of vasculogenesis during embryogenesis and angiogenesis in adult tissues. VEGF is also a vascular permeability factor. VEGF acts via two tyrosine kinase family receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). Recent evidence suggests that neuropilin-1 (NRP1), a receptor involved in neuronal cell guidance, is expressed in endothelial cells, binds to VEGF(165) and enhances the binding of VEGF(165) to VEGFR2. We examined the spatiotemporal expression of vegf isoforms, nrp1 and vegfr2 as well as their interactions in the periimplantation mouse uterus. We observed that vegf(164) is the predominant isoform in the mouse uterus. vegf(164) mRNA accumulation primarily occurred in epithelial cells on days 1 and 2 of pregnancy. On days 3 and 4, the subepithelial stroma in addition to epithelial cells exhibited accumulation of this mRNA. After the initial attachment reaction on day 5, luminal epithelial and stromal cells immediately surrounding the blastocyst exhibited distinct accumulation of vegf(164) mRNA. On days 6-8, the accumulation of this mRNA occurred in both mesometrial and antimesometrial decidual cells. These results suggest that VEGF(164) is available in mediating vascular changes and angiogenesis in the uterus during implantation and decidualization. This is consistent with coordinate expression of vegfr2, and nrp1, a VEGF(164)-specific receptor, in uterine endothelial cells. Their expression was low during the first 2 days of pregnancy followed by increases thereafter. With the initiation and progression of implantation (days 5-8), these genes were distinctly expressed in endothelial cells of the decidualizing stroma. Expression was more intense on days 6-8 at the mesometrial pole, the presumptive site of heightened angiogenesis and placentation. However, the expression was absent in the avascular primary decidual zone immediately surrounding the implanting embryo. Crosslinking experiments showed that (125)I-VEGF(165) binds to both NRP1 and VEGFR2 present in decidual endothelial cells. These results suggest that VEGF(164), NRP1 and VEGFR2 play a role in VEGF-induced vascular permeability and angiogenesis in the uterus required for implantation. genesis 26:213-224, 2000.
植入部位局部血管通透性和血管生成发生的机制尚不清楚。血管内皮生长因子（VEGF）是胚胎发育过程中血管生成和成体组织血管生成的关键调节因子。VEGF也是一种血管通透性因子。VEGF通过两种酪氨酸激酶家族受体发挥作用：VEGFR1（Flt-1）和VEGFR2（KDR/Flk-1）。最近的证据表明，神经纤毛蛋白-1（NRP1），一种参与神经元细胞导向的受体，在内皮细胞中表达，与VEGF（165）结合并增强VEGF（165）与VEGFR2的结合。我们研究了VEGF异构体、nrp1和vegfr2在植入前小鼠子宫中的时空表达及其相互作用。我们观察到vegf（164）是小鼠子宫中的主要异构体。vegf（164）mRNA积累主要发生在妊娠第1天和第2天的上皮细胞中。在第3天和第4天，除上皮细胞外，上皮下基质也出现这种mRNA的积累。在第5天的初始附着反应后，围绕胚泡的腔上皮和基质细胞立即出现vegf（164）mRNA的明显积累。在第6-8天，这种mRNA的积累发生在子宫系膜侧和反子宫系膜侧的蜕膜细胞中。这些结果表明，VEGF（164）在植入和蜕膜化过程中可介导子宫中的血管变化和血管生成。这与vegfr2和nrp1（一种VEGF（164）特异性受体）在子宫内皮细胞中的协同表达一致。它们在妊娠的前两天表达较低，此后增加。随着植入的开始和进展（第5-8天），这些基因在蜕膜化基质的内皮细胞中明显表达。在第6-8天，在子宫系膜极（血管生成和胎盘形成可能增强的部位）表达更强。然而，在围绕植入胚胎的无血管初级蜕膜区没有表达。交联实验表明，（125）I-VEGF（165）与蜕膜内皮细胞中存在的NRP1和VEGFR2都结合。这些结果表明，VEGF（164）、NRP1和VEGFR2在植入所需的VEGF诱导的子宫血管通透性和血管生成中起作用。《发生学》26:213-224，2000年。
