Berndt Sarah, Perrier d'Hauterive Sophie, Blacher Silvia, Péqueux Christel, Lorquet Sophie, Munaut Carine, Applanat Martine, Hervé Marie Astrid, Lamandé Noël, Corvol Pierre, van den Brûle Frédéric, Frankenne Françis, Poutanen Matti, Huhtaniemi Ilpo, Geenen Vincent, Noël Agnès, Foidart Jean-Michel
Laboratory of Tumor and Development Biology, Centre de recherche en cancérologie expérimentale, Université de Liège, Liège, Belgium.
FASEB J. 2006 Dec;20(14):2630-2. doi: 10.1096/fj.06-5885fje. Epub 2006 Oct 25.
Successful embryo development requires an extensive endometrial angiogenesis in proximity of implantation site. The glycoprotein hCG is produced even before implantation by trophoblast in normal pregnancy. In this manuscript, we demonstrate an angiogenic effect of hCG in several in vivo (chick chorioallantoïc membrane, matrigel plug assay, aortic ring assay) and in vitro experimental models. In contrast, human placental lactogen (hPL) did not display angiogenic properties. LH/hCG receptor was detected in endothelial cells by reverse-transcriptase polymerase chain reaction (RT-PCR) and by Western blotting. In mice aortic ring assay, angiostimulation by hCG was abrogated by deletion of LH/hCG receptor (LuRKO mice). Use of recombinant hCG and anti-hCG antibody (Ab) further confirmed the specificity of this angiogenic activity. By using dibutyryl cAMP, adenylate cyclase, or protein kinase A inhibitors, we demonstrate that hCG-mediated angiogenesis involves adenylyl-cyclase-protein kinase A activation. Addition of hCG to endometrial epithelial epithelial cells, but not to cultured endothelial cells, stimulated vascular endothelial growth factor (VEGF). VEGF and hCG also displayed additive activities. Altogether, these data demonstrate that peritrophoblastic angiostimulation may result from a paracrine dialogue between trophoblast, epithelial, and endothelial cells through hCG and VEGF.
成功的胚胎发育需要在着床部位附近有广泛的子宫内膜血管生成。在正常妊娠中，滋养层甚至在着床前就会产生糖蛋白hCG。在本手稿中，我们在几种体内（鸡绒毛尿囊膜、基质胶栓试验、主动脉环试验）和体外实验模型中证明了hCG的血管生成作用。相比之下，人胎盘催乳素（hPL）没有显示出血管生成特性。通过逆转录聚合酶链反应（RT-PCR）和蛋白质印迹法在内皮细胞中检测到LH/hCG受体。在小鼠主动脉环试验中，通过缺失LH/hCG受体（LuRKO小鼠）消除了hCG的血管生成刺激作用。使用重组hCG和抗hCG抗体（Ab）进一步证实了这种血管生成活性的特异性。通过使用二丁酰cAMP、腺苷酸环化酶或蛋白激酶A抑制剂，我们证明hCG介导的血管生成涉及腺苷酸环化酶-蛋白激酶A的激活。将hCG添加到子宫内膜上皮细胞中，但不添加到培养的内皮细胞中，可刺激血管内皮生长因子（VEGF）。VEGF和hCG也显示出相加活性。总之，这些数据表明，滋养层周围的血管生成刺激可能是由于滋养层、上皮细胞和内皮细胞之间通过hCG和VEGF进行旁分泌对话的结果。
