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(Circulation. 2004;109:3035-3041.)
© 2004 American Heart Association, Inc.

Basic Science Reports

In Vivo Evidence of Angiogenesis Induced by Transcription Factor Ets-1

Ets-1 Is Located Upstream of Angiogenesis Cascade

Naotaka Hashiya, MD^*; Nobuo Jo, MD^*; Motokuni Aoki, MD, PhD; Kunio Matsumoto, PhD; Toshikazu Nakamura, PhD; Yasufumi Sato, MD, PhD; Nahoko Ogata, MD, PhD; Toshio Ogihara, MD, PhD; Yasufumi Kaneda, MD, PhD; Ryuichi Morishita, MD, PhD

From the Division of Clinical Gene Therapy (R.M.), Department of Geriatric Medicine (N.H., M.A., T.O.), Division of Gene Therapy Science (Y.K.), and Division of Biochemistry (K.M., T.N.), Graduate School of Medicine, Osaka University, Osaka; the Department of Ophthalmology, Kansai Medical College (N.J., N.O.), Kansai; and the Department of Oncology, Graduate School of Medicine, Tohoku University (Y.S.), Japan.

Correspondence to Ryuichi Morishita, MD, PhD, Professor, Division of Clinical Gene Therapy, Osaka University Medical School, 2-2 Yamada-oka, Suita 565-0871, Japan. E-mail morishit{at}gts.med.osaka-u.ac.jp

Received October 8, 2002; de novo received December 10, 2003; revision received March 4, 2004; accepted March 15, 2004.

Background— A transcription factor, ets-1, regulates the transcription of metalloproteinase genes, the activity of which is necessary for matrix degradation and the migration of endothelial cells. However, no study has demonstrated that ets-1 itself has an angiogenic action in vivo. Thus, we examined (1) the effects of overexpression of the ets-1 gene on angiogenesis in a rat hindlimb ischemia model, and (2) how ets-1 induced angiogenesis.

Methods and Results— In this study, we used the HVJ-liposome method, which is highly effective for transfection, to transfect the human ets-1 gene. At 4 weeks after transfection, the capillary density and blood flow were significantly increased in a hindlimb transfected with the human ets-1 gene compared with control. These data clearly demonstrated that ets-1 has the ability to stimulate angiogenesis in vivo. To elucidate the molecular mechanisms by which ets-1 induced angiogenesis, we focused especially on the expression of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), potent angiogenic growth factors, because the promoter regions of both genes contain ets binding sites. Interestingly, overexpression of ets-1 upregulated both tissue HGF and VEGF concentrations in rat hindlimb. More importantly, administration of neutralizing antibody against HGF and VEGF attenuated the increase in blood flow and BrdU-positive cells induced by ets-1. Upregulation of HGF and VEGF by ets-1 was also confirmed by in vitro experiments using human vascular smooth muscle cells.

Conclusions— The present study demonstrated that ets-1 regulated angiogenesis through the induction of angiogenic growth factors (VEGF and HGF). Overexpression of ets may provide a new therapeutic strategy to treat peripheral arterial disease.

Key Words: angiogenesis • gene therapy • growth substances • viruses

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