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Molecular and Cellular Biology, November 2001, p. 7218-7230, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7218-7230.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Transforming Growth Factor beta 1 (TGF-beta 1) Promotes Endothelial Cell Survival during In Vitro Angiogenesis via an Autocrine Mechanism Implicating TGF-alpha Signaling

Francesc Viñals* and Jacques Pouysségur*

Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543-Centre Antoine Lacassagne, 06189 Nice Cedex 2, France

Received 2 March 2001/Returned for modification 19 April 2001/Accepted 6 August 2001

Mouse capillary endothelial cells (1G11 cell line) embedded in type I collagen gels undergo in vitro angiogenesis. Cells rapidly reorganize and form capillary-like structures when stimulated with serum. Transforming growth factor beta 1 (TGF-beta 1) alone can substitute for serum and induce cell survival and tubular network formation. This TGF-beta 1-mediated angiogenic activity depends on phosphatidylinositol 3-kinase (PI3K) and p42/p44 mitogen-activated protein kinase (MAPK) signaling. We showed that specific inhibitors of either pathway (wortmannin, LY-294002, and PD-98059) all suppressed TGF-beta 1-induced angiogenesis mainly by compromising cell survival. We established that TGF-beta 1 stimulated the expression of TGF-alpha mRNA and protein, the tyrosine phosphorylation of a 170-kDa membrane protein representing the epidermal growth factor (EGF) receptor, and the delayed activation of PI3K/Akt and p42/p44 MAPK. Moreover, we showed that all these TGF-beta 1-mediated signaling events, including tubular network formation, were suppressed by incubating TGF-beta 1-stimulated endothelial cells with a soluble form of an EGF receptor (ErbB-1) or tyrphostin AG1478, a specific blocker of EGF receptor tyrosine kinase. Finally, addition of TGF-alpha alone poorly stimulated angiogenesis; however, by reducing cell death, it strongly potentiated the action of TGF-beta 1. We therefore propose that TGF-beta 1 promotes angiogenesis at least in part via the autocrine secretion of TGF-alpha , a cell survival growth factor, activating PI3K/Akt and p42/p44 MAPK.


* Corresponding author. Present address for Francese Viñals: Facultad de Odontologia, Universitat de Barcelona, 08907 L'Hospitalet de Llobregat, Barcelona, Spain. E-mail: fvinals{at}bell.ub.es. Mailing address for Jacques Pouysségur: Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543-Centre Antoine Lacassagne, 33 Av. Valombrose, 06189 Nice Cedex 2, France. Phone: (33) 492 03 1222. Fax: (33) 492 03 1225. E-mail: pouysseg{at}unice.fr.


Molecular and Cellular Biology, November 2001, p. 7218-7230, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7218-7230.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.



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