Zygmunt Marek, Herr Friederike, Keller-Schoenwetter Stefanie, Kunzi-Rapp Karin, Münstedt Karsten, Rao C V, Lang Uwe, Preissner Klaus T
Department of Obstetrics and Gynecology, Justus Liebig University, Klinikstrasse 32, D-35385 Giessen, Germany.
J Clin Endocrinol Metab. 2002 Nov;87(11):5290-6. doi: 10.1210/jc.2002-020642.
Angiogenesis and vascular remodeling are crucial processes in tumor invasion and metastasis as well as in embryo implantation and normal development of the placenta. We have previously shown that hCG expressed in trophoblast and various malignant tumors promotes cellular motility and that uterine endothelium expresses hCG/LH receptor in vivo. In this study hCG was proposed to promote angiogenesis. A three-dimensional in vitro angiogenesis system consisting of uterine microvascular endothelial cells seeded on microcarriers and entrapped in a fibrin matrix was used to study the influence of hCG on neovascularization. Physiological concentrations of hCG (5-50,000 mU/ml) significantly increased in vitro capillary formation (up to 2.5-fold) and migration of endothelial cells in a Boyden chamber assay (up to 3.6-fold) in a dose-dependent manner, whereas hCG had no effect on cell proliferation. In vivo, hCG induced neovascularization in the chicken chorioallantoic membrane assay comparable to the activity of vascular endothelial growth factor. hCG-secreting tumors (choriocarcinoma, endometrium, and ovarian carcinoma) promoted in vitro neovascularization (up to 3-fold), whereas hCG-neutralizing antibody, pertussis toxin (G protein inhibitor), or GRGDTP peptide (integrin antagonist), respectively, abolished both tumor- and hCG-induced capillary sprout formation. Our data indicate a novel function for hCG in uterine adaptation to early pregnancy as well as in tumor development and underline the importance of hCG as an as yet unrecognized angiogenic factor.
血管生成和血管重塑是肿瘤侵袭和转移以及胚胎植入和胎盘正常发育过程中的关键过程。我们之前已经表明，滋养层细胞和各种恶性肿瘤中表达的hCG可促进细胞运动，并且子宫内皮细胞在体内表达hCG/LH受体。在本研究中，hCG被认为可促进血管生成。使用一种三维体外血管生成系统，该系统由接种在微载体上并包裹在纤维蛋白基质中的子宫微血管内皮细胞组成，用于研究hCG对新血管形成的影响。生理浓度的hCG（5 - 50,000 mU/ml）以剂量依赖的方式显著增加体外毛细血管形成（高达2.5倍）以及在Boyden小室试验中内皮细胞的迁移（高达3.6倍），而hCG对细胞增殖没有影响。在体内，hCG在鸡绒毛尿囊膜试验中诱导的新血管形成与血管内皮生长因子的活性相当。分泌hCG的肿瘤（绒毛膜癌、子宫内膜癌和卵巢癌）促进体外新血管形成（高达3倍），而hCG中和抗体、百日咳毒素（G蛋白抑制剂）或GRGDTP肽（整合素拮抗剂）分别消除肿瘤和hCG诱导的毛细血管芽形成。我们的数据表明hCG在子宫对早期妊娠的适应以及肿瘤发展中具有新功能，并强调了hCG作为一种尚未被认识的血管生成因子的重要性。
