Characterization of human chorionic gonadotropin as a novel angiogenic factor.
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.
Zygmunt
Marek
M
Department of Obstetrics and Gynecology, Justus Liebig University, Klinikstrasse 32, D-35385 Giessen, Germany. marek.t.zygmunt@gyn.med.uni-giessen.de
Herr
Friederike
F
Keller-Schoenwetter
Stefanie
S
Kunzi-Rapp
Karin
K
Münstedt
Karsten
K
Rao
C V
CV
Lang
Uwe
U
Preissner
Klaus T
KT
D000482:Allantois / Q000098:blood supply; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D002196:Capillaries / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002645:Chickens; D002822:Choriocarcinoma; D002823:Chorion / Q000098:blood supply; D006063:Chorionic Gonadotropin / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D018920:Coculture Techniques; D016889:Endometrial Neoplasms; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010051:Ovarian Neoplasms; D037342:Pertussis Toxin / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000098:blood supply*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000906:Antibodies; D006063:Chorionic Gonadotropin; D016228:Endothelial Growth Factors; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003994:Bucladesine; D037342:Pertussis Toxin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate