Abstract:
AIMS/HYPOTHESIS:As vascular endothelial growth factor (VEGF) plays a pivotal role in the development of diabetic retinopathy, inhibition of angiogenesis induced by VEGF is crucial to treat diabetic retinopathy. HGF (hepatocyte growth factor)/NK4, containing the N-terminal hairpin domain and the four subsequent kringle domains of HGF, is considered as a specific antagonist for HGF. Our aim was to explore the inhibitory effects of HGF/NK4 on angiogenesis induced by VEGF. METHODS:To analyze the in vivo angiogenesis, we used rabbit corneal micropocket assay. Proliferation and migration of human endothelial cells, expression of ets-1, an essential transcription factor for angiogenesis, and the phosphorylation of extracellular signal-regulated kinase (ERK) was examined with or without HGF/NK4. RESULTS:Using corneal micropocket assay, in vivo administration of HGF/NK4 inhibited angiogenesis induced by VEGF. HGF/NK4 inhibited proliferation and migration of human endothelial cells induced by VEGF in a dose-dependent manner. Interestingly, VEGF-mediated phosphorylation of ERK was significantly attenuated by HGF/NK4. Of importance, HGF/NK4 attenuated the increase in ets-1 protein stimulated by VEGF. Nevertheless, HGF/NK4 did not affect phosphorylation of VEGF receptor-2 [kinase domain region (KDR)/foetal liver kinase (Flk)-1]. Although tyrosine phosphatase inhibitor (Na(3)VO(4)), or okadaic acid, serine-threonin kinase inhibitor, did not prevent the inhibition of ERK phosphorylation by HGF/NK4, co-incubation of HGF/NK4 with VEGF significantly diminished mitogen-activated protein (MAP) ERK kinase (MEK) phosphorylation (p<0.01). CONCLUSIONS/INTERPRETATION:Overall, HGF/NK4 inhibited angiogenesis induced by VEGF through inhibition of phosphorylation of ERK and ets-1 expression in in vitro cultured endothelial cells and in vivo rabbit model.
journal_name
Diabetologiajournal_title
Diabetologiaauthors
Nakabayashi M,Morishita R,Nakagami H,Kuba K,Matsumoto K,Nakamura T,Tano Y,Kaneda Ydoi
10.1007/s00125-002-0954-ysubject
Has Abstractpub_date
2003-01-01 00:00:00pages
115-23issue
1eissn
0012-186Xissn
1432-0428journal_volume
46pub_type
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