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(Circulation Research. 2002;91:923.)
© 2002 American Heart Association, Inc.

Integrative Physiology

Fibroblast Growth Factor-2 Gene Transfer Can Stimulate Hepatocyte Growth Factor Expression Irrespective of Hypoxia-Mediated Downregulation in Ischemic Limbs

Mitsuho Onimaru, Yoshikazu Yonemitsu, Mitsugu Tanii, Kazunori Nakagawa, Ichiro Masaki, Shinji Okano, Hiroaki Ishibashi, Kanemitsu Shirasuna, Mamoru Hasegawa, Katsuo Sueishi

From the Division of Pathophysiological and Experimental Pathology (M.O., Y.Y., M.T., K.N., I.M., S.O., K.S.), Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Second Department of Oral and Maxillofacial Surgery (M.O., H.I., K.S.), Graduate School of Dental Sciences, Kyushu University, Fukuoka, Japan; and DNAVEC Research Inc (M.H.), Tsukuba, Ibaraki, Japan.

Correspondence to Yoshikazu Yonemitsu, MD, PhD, FAHA, Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail yonemitu{at}pathol1.med.kyushu-u.ac.jp

Hepatocyte growth factor (HGF) is a potent angiogenic polypeptide that stimulates angiogenesis. Transcriptional regulation of HGF, however, has not been fully defined, with the exception of the hypoxia-mediated downregulation in cultured cells. In the present study, we report that angiogenic growth factors, including HGF, were upregulated in a murine model of critical limb ischemia in vivo, a finding that was in conflict with previous in vitro data. Mice deficient in basic fibroblast growth factor-2 (FGF-2) showed reduced induction of HGF protein in ischemic muscles, and overexpression of FGF-2 via gene transfer stimulated endogenous HGF, irrespective of the presence of ischemia. In culture, FGF-2 rapidly stimulated HGF mRNA, and a sustained expression was evident in the time course in vascular smooth muscle cells and fibroblasts. FGF-2–mediated induction of HGF was fully dependent on the mitogen-activated protein kinase pathway yet was not affected by either hypoxia or a protein kinase A inhibitor. In the early expression, FGF-2 directly stimulated HGF mRNA without the requirement of new protein synthesis, whereas sustained induction of HGF in the later phase was partly mediated by platelet-derived growth factor-AA. Furthermore, in vivo overexpression of FGF-2 significantly improved the blood perfusion, and the effect was abolished by systemic blockade of HGF in ischemic limbs. This is the first demonstration of a regulational mechanism of HGF expression via FGF-2 that was independent of the presence of hypoxia. The harmonized therapeutic effects of FGF-2, accompanied with the activity of endogenous HGF, may provide a beneficial effect for the treatment of limb ischemia.

Key Words: fibroblast growth factor-2 • hepatocyte growth factor • ischemia

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