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(Circulation. 1999;100:II-301.)
© 1999 American Heart Association, Inc.

Aortic and Peripheral Vascular Surgery

Potential Role of Hepatocyte Growth Factor, a Novel Angiogenic Growth Factor, in Peripheral Arterial Disease

Downregulation of HGF in Response to Hypoxia in Vascular Cells

Shin-ichiro Hayashi, MD, PhD; Ryuichi Morishita, MD, PhD; Shigefumi Nakamura, MD; Kei Yamamoto, MD; Atsushi Moriguchi, MD, PhD; Tomokazu Nagano, PhD; Mutsuo Taiji, PhD; Hiroshi Noguchi, PhD; Kunio Matsumoto, PhD; Toshikazu Nakamura, PhD; Jitsuo Higaki, MD, PhD; Toshio Ogihara, MD, PhD

From the Department of Geriatric Medicine, Osaka University Medical School; Sumitomo Pharmaceutical Company (T. Nagano, M.T., H.N.), Osaka, Japan; and the Division of Biochemistry (K.M., T. Nakamura), Department of Oncology, Biomedical Research Center, Osaka University Medical School, Japan.

Correspondence to Ryuichi Morishita, MD, PhD, Associate Professor, Department of Geriatric Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita 565, Japan. E-mail morishit{at}geriat.med.osaka-u.ac.jp

Background—Although hepatocyte growth factor (HGF), a novel angiogenic growth factor, plays an important role in angiogenesis, regulation of local HGF production under hypoxia has not yet been clarified in vascular smooth muscle cells (VSMC) and endothelial cells (EC). Thus, we have studied the role of HGF in hypoxia-induced endothelial injury and the regulation of local vascular HGF expression in response to hypoxia.

Methods and Results—HGF attenuated hypoxia-induced endothelial cell death. Importantly, hypoxic treatment of EC resulted in a significant decrease in local HGF production according to the severity of hypoxia and increased VEGF. Similarly, hypoxia significantly decreased in mRNA and protein of HGF and increased VEGF production in VSMC. In organ culture system, local HGF production was also significantly decreased by hypoxia (P<0.01). Downregulation of HGF by hypoxia is due to a significant decrease in cAMP, as hypoxic treatment decreased cAMP, a stimulator of HGF. Although active TGF-ß, a suppressor of HGF, was increased at 72 hours after hypoxic treatment, treatment of anti-TGF-ß antibody did not attenuate decreased HGF production. Finally, rHGF was intra-arterially administered into unilateral hind limb ischemia rabbits, to evaluate in vivo angiogenic activity. Of importance, a single intra-arterial administration of rHGF reduced severe necrosis due to ischemia in rabbit muscle, accompanied by a significant increase in angiographic score (P<0.01).

Conclusions—Overall, these data demonstrated that hypoxic treatment of vascular cells significantly downregulated HGF production due to decreased cAMP, suggesting their potential roles in the pathophysiology of ischemic diseases. Moreover, administration of rHGF induced therapeutic angiogenesis, accompanied by improvement of necrotic changes in the ischemic hind limb model, as cytokine supplement therapy for peripheral arterial disease.

Key Words: endothelium • peripheral vascular disease • angiogenesis • myocardial infarction • remodeling