Published Online
on March 3, 2003

A more recent version of this article appeared on March 18, 2003

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Submitted on October 28, 2002
Accepted on December 5, 2002

Angiogenic Property of Hepatocyte Growth Factor Is Dependent on Upregulation of Essential Transcription Factor for Angiogenesis, ets-1

Naruya Tomita MD, PhD, Ryuichi Morishita MD, PhD^*, Yoshiaki Taniyama MD, Hiromi Koike , Motokuni Aoki MD, PhD, Hideo Shimizu MD, Kunio Matsumoto PhD, Toshikazu Nakamura PhD, Yasufumi Kaneda MD, PhD, and Toshio Ogihara MD, PhD

From the Department of Geriatric Medicine (N.T., R.M., Y.T., M.A., H.S., T.O.), Division of Gene Therapy Science (R.M., H.K., Y.K.), and Division of Biochemistry, Department of Oncology, Biomedical Research Center (K.M., T.N.), Osaka University Medical School, Japan.

^* To whom correspondence should be addressed. E-mail: morishit{at}gts.med.osaka-u.ac.jp.

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.

Methods and 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.

Key words: angiogenesis • metalloproteinases • cells • growth substances

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