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(Circulation. 2002;106:I-264.)
© 2002 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

In Vivo Gene Transfection With Hepatocyte Growth Factor via the Pulmonary Artery Induces Angiogenesis in the Rat Lung

Masamichi Ono, MD; Yoshiki Sawa, MD, PhD; Kunio Matsumoto, PhD; Toshikazu Nakamura, PhD; Yasufumi Kaneda, MD, PhD; Hikaru Matsuda, MD, PhD

From the Division of Cardiovascular Surgery, Department of Surgery (M.O., Y.S., H.M.), Division of Molecular Regenerative Medicine, Course of Advanced Medicine (K.M., T.M.), and ^cDepartment of Gene Therapy Science (Y.K.), Osaka University Graduate School of Medicine, Osaka, Japan.

Correspondence to Hikaru Matsuda, MD, Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, 2–2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail matsuda{at}surg1.med.osaka-u.ac.jp

Background Recent studies have demonstrated that gene transfer with hepatocyte growth factor (HGF) induces angiogenesis for coronary and peripheral artery diseases. We investigated the ability of gene transfer with human HGF to induce angiogenesis in the rat lung.

Methods and Results The left lung was selectively transfected with a cDNA encoding human HGF via the left pulmonary artery, using the HVJ-liposome method (H group); rats transfected with the same vector lacking the HGF gene served as controls (C group). HGF gene transfer significantly increased the capillary density in the left lung compared with the C group 7 days after transfection (15.0±1.3 versus 8.0±1.7 mm², P<0.01). The left to right average blood perfusion ratio detected by laser Doppler imaging increased significantly in the H group 14 days after transfection (1.12±0.09 versus 0.91±0.11, P<0.01). A right pulmonary artery clamp test, in which only the left lung received all the pulmonary blood flow from the right ventricle, revealed that the increase in right ventricular pressure was significantly attenuated in the H group compared with the C group 7 days after transfection (8.6±3.5 versus 15.3±2.8 mm Hg, P<0.01).

Conclusions Trans-pulmonary arterial transfer of the human HGF gene into the left lung increased capillary density and blood perfusion, and decreased vascular resistance when blood flow increased. These results suggest therapeutic angiogenesis induced by HGF gene expression in the lung may be found suitable in treating subjects with decreased pulmonary vasculature or increased pulmonary vascular resistance.

Key Words: angiogenesis • gene therapy • pulmonary vasculature • growth factor • remodeling