title: Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-β receptor activation.
abstract: Embryo implantation requires extensive angiogenesis at the maternal-fetal interface. Hyperglycosylated human chorionic gonadotropin (hCG-H), a trophoblast invasive signal produced by extravillous cytotrophoblasts and by choriocarcinoma, was evaluated for its angiogenic role. hCG-H was purified by HPLC from choriocarcinoma supernatant, and the glycosylation pattern was determined by 2D gel analysis. Angiogenesis models used were aortic ring assay with wild-type and LHCGR-knockout mice, endothelial and mural cell proliferation, and migration assays. The TGF-β signaling pathway was studied by coimmunoprecipitation, competitive binding, TGF-β reporter gene assays, and Smad immunoblotting. hCG-H displayed a potent angiogenic effect [3.2-fold increase of number of vessel intersections in wild-type aortic rings (11.406 to 36.964)]. hCG-H-induced angiostimulation was independent of the classic hCG signaling pathway since it persisted in LHCGR-knockout mice [4.73-fold increase of number of vessel intersections (10.826 to 51.288)]. Using TGF-β signaling inhibitors, Tβ-RII was identified as the hCG-H receptor responsible for its angiogenic switch. hCG-H exposure enhanced phosphorylation of Smad 2 in endothelial and mural cells and genomic activation of Smad-responsive elements. Interaction between hCG-H and Tβ-RII was demonstrated by coimmunoprecipitation and binding competition with (125)I-TGF-β. This new paracrine interaction between trophoblast and endothelial cells through the hCG-H and the TGF-β receptor complex plays a key role in angiogenesis associated with placental development and tumorigenesis.
authors.affiliation: Institut National de Santé et de Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé -767, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Berndt
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.forename: Carine
authors.initials: C
authors.lastname: Munaut
authors.forename: Julien
authors.initials: J
authors.lastname: Detilleux
authors.forename: Sophie
authors.initials: S
authors.lastname: Perrier d'Hauterive
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.forename: Danièle
authors.initials: D
authors.lastname: Evain-Brion
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
authors.forename: Thierry
authors.initials: T
authors.lastname: Fournier
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000378:metabolism*; D010064:Embryo Implantation / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006031:Glycosylation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D011974:Receptors, LH / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D006063:Chorionic Gonadotropin; D011974:Receptors, LH; D018125:Receptors, Transforming Growth Factor beta