Hepatocyte growth factor/scatter factor promotes retinal angiogenesis through increased urokinase expression.
OBJECTIVE
The purpose of this study was to determine the role of hepatocyte growth factor (HGF) and c-Met in the initiation and development of retinal neovascularization and to determine whether inhibition of this system can suppress the extent of angiogenesis in an animal model.


METHODS
Retinal tissues from animals with oxygen-induced neovascularization were analyzed for HGF and c-Met expression and localization. The effect of HGF on the migratory and invasive behavior of isolated retinal endothelial cells was quantitated, and the role of the extracellular proteinase urokinase in facilitating this process was determined. Mice were treated with intraocular injections of anti-c-Met antibody, and the extent of neovascularization was quantitated.


RESULTS
HGF and c-Met were upregulated in the retinas of mice with hypoxia-induced retinal neovascularization. HGF was active, as evidenced by the increased presence of the phosphorylated form of c-Met in the tissues. c-Met was localized to various cell types in the retina, including vascular cells, and HGF was produced by cells in the ganglion and inner nuclear layers. HGF stimulated the secretion of urokinase and its receptor, uPAR, in isolated retinal endothelial cells. HGF increased the migratory and invasive capacity of these cells, which could be inhibited by the disruption of urokinase/uPAR interactions with the A6 peptide. Inhibition of c-Met activation in vivo resulted in a 70% decrease in retinal angiogenesis and a 40% decrease in urokinase activity in the retina.


CONCLUSIONS
These studies suggest that HGF may play an important role in the initial stages of retinal angiogenesis by stimulating a migratory phenotype in endothelial cells mediated by increased urokinase activity.
Colombo
Elizabeth S
ES
Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Menicucci
Gina
G
McGuire
Paul G
PG
Das
Arup
A
D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D019084:Fluorescent Antibody Technique, Indirect; D017228:Hepatocyte Growth Factor / Q000494:pharmacology / Q000502:physiology*; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000633:toxicity; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D012165:Retinal Ganglion Cells / Q000378:metabolism; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
C524899:Plaur protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D014568:Urokinase-Type Plasminogen Activator; D010100:Oxygen