Bausero P, Cavaillé F, Méduri G, Freitas S, Perrot-Applanat M
INSERM U 460, Remodelage Vasculaire, CHU Xavier Bichât, 75870 Paris Cedex, France.
Angiogenesis. 1998;2(2):167-82. doi: 10.1023/a:1009292506879.
Vascular endothelial growth factor (VEGF) is an endothelium-specific growth factor with potent angiogenic activity and a stimulator of microvascular permeability. Because endometrial cyclic development is associated with vascular growth, we examined the expression of VEGF protein throughout the menstrual cycle and studied the regulation of VEGF mRNA by ovarian steroids in isolated human endometrial stromal cells. VEGF was localized immunohistochemically in glandular epithelial cells and in the surrounding stroma, as well as in capillaries and spiral arterioles, a localization which has not been described before. The strongest immunoreactivity for VEGF on endothelial cells was detected in the late proliferative and secretory phases. The localization of VEGF bound to the endothelium correlates with the presence of flt-1 and flk/KDR receptors on vascular structures, including capillary strands which have not yet formed a lumen, present during the mid-secretory period, which corresponds to a high estroprogestin influence and to implantation. Heparinase treatment of the sections decreases the staining intensity of VEGF bound to endothelial cells, suggesting that VEGF also binds to heparin-like molecules on the cell surface. These new results demonstrate a major role of VEGF on capillary formation and on hyperpermeability and edema during the menstrual cycle. Consistent with these in vivo observations, the treatment of isolated endometrial stromal cells with estradiol (E2) or E2 plus progesterone, significantly increased VEGF mRNA over the control value in a dose-dependent manner; the VEGF mRNA response to E2 was rapid (3h) and persisted with continuous estradiol treatment up to 12 days. Three species, VEGF_121, VEGF165 and VEGF189, were observed upon hormonal stimulation. The estradiol up-regulation of VEGF response did not require de novo protein synthesis as it was not blocked by cycloheximide. Also, the ability of the pure anti-estrogen ICI 182,780 to significantly block induction of VEGF mRNA by E2 suggests estrogen receptor-mediated transcriptional regulation. These results demonstrate that VEGF is an estrogen-responsive angiogenic factor that acts on vascular endothelium in a paracrine fashion, as previously suggested. This growth factor controls angiogenesis and hyperpermeability required for adequate receptivity to implantation of the cycling human endometrium. These findings also raise the possibility that estrogen effects on uterine edema, proliferation and tumoral transformation may involve local increases in tissue VEGF production.
血管内皮生长因子（VEGF）是一种具有强大血管生成活性的内皮特异性生长因子，也是微血管通透性的刺激因子。由于子宫内膜的周期性发育与血管生长相关，我们研究了整个月经周期中VEGF蛋白的表达，并在分离的人子宫内膜基质细胞中研究了卵巢甾体激素对VEGF mRNA的调控。VEGF通过免疫组织化学定位在腺上皮细胞及其周围的基质中，以及毛细血管和螺旋小动脉中，这种定位此前尚未见报道。在内皮细胞上，VEGF最强的免疫反应性在增殖晚期和分泌期被检测到。与内皮细胞结合的VEGF的定位与血管结构上flt-1和flk/KDR受体的存在相关，这些血管结构包括在分泌中期出现的尚未形成管腔的毛细血管束，这一时期对应着高雌激素孕激素影响和着床。对切片进行肝素酶处理会降低与内皮细胞结合的VEGF的染色强度，这表明VEGF也与细胞表面的类肝素分子结合。这些新结果表明VEGF在月经周期中对毛细血管形成、高通透性和水肿起主要作用。与这些体内观察结果一致，用雌二醇（E2）或E2加孕酮处理分离的子宫内膜基质细胞，可使VEGF mRNA显著高于对照值，并呈剂量依赖性增加；VEGF mRNA对E2的反应迅速（3小时），且在持续给予雌二醇处理长达12天的过程中持续存在。在激素刺激后观察到三种VEGF亚型，即VEGF_121、VEGF165和VEGF189。E2对VEGF反应的上调不需要从头合成蛋白质，因为它不受环己酰亚胺的阻断。此外，纯抗雌激素ICI 182,780能够显著阻断E2对VEGF mRNA的诱导，这表明是雌激素受体介导的转录调控。这些结果表明，如先前所提示的，VEGF是一种以旁分泌方式作用于血管内皮的雌激素反应性血管生成因子。这种生长因子控制着血管生成和高通透性，而这对于周期性人子宫内膜对着床的充分接受性是必需的。这些发现还增加了一种可能性，即雌激素对子宫水肿、增殖和肿瘤转化的影响可能涉及组织VEGF产生的局部增加。
