Transforming growth factor beta2 inhibition of hepatocyte growth factor-induced endothelial proliferation and migration.
Angiogenesis is a highly controlled event which depends on the proper equilibrium of activators and inhibitors present within the microenvironment. Hepatocyte Growth Factor (HGF) activates migration and proliferation of endothelial cells and is angiogenic, acting through the tyrosine kinase receptor encoded by the Met protooncogene. To get insights into the molecular mechanisms involved in HGF-induced angiogenesis, we searched for cDNAs differentially expressed in human endothelial cells exposed to HGF, a potent angiogenic factor. We found that HGF-treated endothelial cells upregulated the expression of Transforming Growth Factor (TGF) beta2. To understand the significance of this finding, we cultured endothelial cells with HGF and TGF beta2 simultaneously. We found that TGF beta2 impairs HGF-dependent proliferative and migratory responses. TGF beta2 did not prevent the tyrosine phosphorylation of Met, but it inhibited some signalling pathways activated by HGF. We show that endothelial proliferation induced by HGF required the activation of the MAPK cascade, while HGF-induced endothelial migration was dependent on the tyrosine phosphorylation of Src. Indeed, TGF beta2 inhibited HGF effects because it prevented HGF-induced MAP kinase activation and tyrosine phosphorylation of Src. We suggest that the induction of TGF beta2 by HGF in endothelial cells may represent a physiologic mechanism to counterbalance HGF angiogenic activity.
Manganini
M
M
Department of Biomedical Sciences, University of Milan. Via Olgettina, 60 Milano, Italy.
Maier
J A
JA
D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors*; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D019061:src-Family Kinases / Q000502:physiology
D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D019061:src-Family Kinases; D020929:Mitogen-Activated Protein Kinase Kinases