Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-beta receptor activation.

[en] 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, Tbeta-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 Tbeta-RII was demonstrated by coimmunoprecipitation and binding competition with (125)I-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.

Disciplines :

Reproductive medicine (gynecology, andrology, obstetrics)

Author, co-author :

Berndt, Sarah

Blacher, Silvia ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

Munaut, Carine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

Detilleux, Julien

Perrier d'Hauterive, Sophie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Embryologie

Huhtaniemi, Ilpo

Evain-Brion, Daniele

Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme

Fournier, Thierry

Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique

Language :

English

Title :

Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-beta receptor activation.

Publication date :

2013

Journal title :

FASEB Journal

ISSN :

0892-6638

eISSN :

1530-6860

Publisher :

Federation of American Society for Experimental Biology, Bethesda, United States - Maryland

Volume :

Issue :

Pages :

1309-21

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 17 January 2013

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