Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1.
BACKGROUND
Although hepatocyte growth factor (HGF) is an angiogenic growth factor, it is still unclear how it exerts its angiogenic effects. Thus, we focused on the role of an essential transcription factor for angiogenesis, ets-1. In this study, we addressed the following specific questions: (1) what genes responsible for angiogenesis can be regulated by HGF and (2) whether upregulation of gene expression for angiogenesis is dependent on ets-1.


RESULTS
In human endothelial cells, HGF significantly stimulated the matrix-degrading pathway, such as the production of matrix metalloprotease-1 (MMP-1) through its specific receptor, c-met. In addition, HGF also significantly increased HGF itself and its specific receptor, c-met. Moreover, HGF significantly increased the transcription activity and mRNA expression of ets-1 in a time-dependent manner. Importantly, transfection of antisense ets-1 oligodeoxynucleotides (ODN) resulted in a significant reduction in MMP-1, HGF and c-met. Interestingly, HGF also stimulated ets-1 mRNA in vascular smooth muscle cells, similar to endothelial cells. Of importance, transfection of antisense ets-1 ODN resulted in a significant decrease in vascular endothelial growth factor (VEGF) and HGF expression, whereas HGF stimulated both HGF and VEGF expression. Moreover, in vivo transfection of ets-1 antisense ODN resulted in an inhibition of angiogenesis induced by the HGF gene in a rat ischemic hindlimb model.


CONCLUSIONS
Here, we demonstrated that HGF stimulated the expression of MMP-1, VEGF, HGF itself, and c-met in human endothelial cells and vascular smooth muscle cells. Upregulation of angiogenesis-related genes was largely dependent on the induction of ets, especially ets-1. These data provide new information about the mechanisms of angiogenesis.
Tomita
Naruya
N
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.
Morishita
Ryuichi
R
Taniyama
Yoshiaki
Y
Koike
Hiromi
H
Aoki
Motokuni
M
Shimizu
Hideo
H
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Kaneda
Yasufumi
Y
Ogihara
Toshio
T
D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
C494041:ETS1 protein, human; C494043:Ets1 protein, rat; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor