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PMID: 11585905 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Transforming growth factor beta1 (TGF-beta1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-alpha signaling.

Molecular and cellular biology ·Vol. 21 ·No. 21 ·2001-11-00 ·Pages 7218-30

Viñals F, Pouysségur J

Abstract

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 beta1 (TGF-beta1) alone can substitute for serum and induce cell survival and tubular network formation. This TGF-beta1-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-beta1-induced angiogenesis mainly by compromising cell survival. We established that TGF-beta1 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-beta1-mediated signaling events, including tubular network formation, were suppressed by incubating TGF-beta1-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-beta1. We therefore propose that TGF-beta1 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.

MeSH Terms
Androstadienes/pharmacology Animals Blotting, Northern Blotting, Western Cell Death Cell Line Cell Survival Cells, Cultured Chromones/pharmacology Collagen Type I/metabolism Endothelium, Vascular/cytology,metabolism Enzyme Activation Enzyme Inhibitors/pharmacology Flavonoids/pharmacology Humans Mice Mitogen-Activated Protein Kinase 1/metabolism Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases/metabolism Morpholines/pharmacology Neovascularization, Physiologic Phosphatidylinositol 3-Kinases/metabolism Phosphorylation Protein Binding Quinazolines RNA, Messenger/metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Time Factors Transforming Growth Factor alpha/metabolism Transforming Growth Factor beta/metabolism Transforming Growth Factor beta1 Tyrphostins/pharmacology Wortmannin
Chemicals
Androstadienes Chromones Collagen Type I Enzyme Inhibitors Flavonoids Morpholines Quinazolines RNA, Messenger TGFB1 protein, human Tgfb1 protein, mouse Transforming Growth Factor alpha Transforming Growth Factor beta Transforming Growth Factor beta1 Tyrphostins RTKI cpd 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one Phosphatidylinositol 3-Kinases Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one Wortmannin
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Viñals F
Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543-Centre Antoine Lacassagne, 06189 Nice Cedex 2, France.
Pouysségur J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.21.21.7218-7230.2001
Published
2001-11-00
Pages
7218-30
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC99897
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.21.21.7218-7230.2001 PMC Full Text View journal details
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