A1 Refereed original research article in a scientific journal
Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-β receptor activation
Authors: Berndt Sarah, Blacher Silvia, Munaut Carine, Detilleux Julien, d'Hauterive Sophie Perrier, Huhtaniemi Ilpo, Evain-Brion Danièle, Noël Agnès, Fournier Thierry, Foidart Jean-Michel
Publication year: 2013
Journal: FASEB Journal
Number in series: 4
Volume: 27
Issue: 4
First page : 1309
Last page: 1321
Number of pages: 13
ISSN: 0892-6638
DOI: https://doi.org/10.1096/fj.12-213686
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-beta signaling pathway was studied by coimmunoprecipitation, competitive binding, TGF-beta 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-beta signaling inhibitors, T beta-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 T beta-RII was demonstrated by coimmunoprecipitation and binding competition with I-125-TGF-beta. This new paracrine interaction between trophoblast and endothelial cells through the hCG-H and the TGF-beta receptor complex plays a key role in angiogenesis associated with placental development and tumorigenesis.-Berndt, S., Blacher, S., Munaut, C., Detilleux, J., Perrier d'Hauterive, S., Huhtaniemi, I., Evain-Brion, D., Noel, A., Fournier, T., Foidart, J.-M. Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-beta receptor activation. FASEB J. 27, 1309-1321 (2013). www.fasebj.org
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-beta signaling pathway was studied by coimmunoprecipitation, competitive binding, TGF-beta 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-beta signaling inhibitors, T beta-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 T beta-RII was demonstrated by coimmunoprecipitation and binding competition with I-125-TGF-beta. This new paracrine interaction between trophoblast and endothelial cells through the hCG-H and the TGF-beta receptor complex plays a key role in angiogenesis associated with placental development and tumorigenesis.-Berndt, S., Blacher, S., Munaut, C., Detilleux, J., Perrier d'Hauterive, S., Huhtaniemi, I., Evain-Brion, D., Noel, A., Fournier, T., Foidart, J.-M. Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-beta receptor activation. FASEB J. 27, 1309-1321 (2013). www.fasebj.org
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