Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets.
The feasibility of a novel therapeutic strategy using angiogenic growth factors to expedite and/or augment collateral artery development has recently entered the realm of treatment of ischemic diseases. Hepatocyte growth factor (HGF) is a novel member of endothelium-specific growth factors whose mitogenic activity on endothelial cells is very potent. Although it has been demonstrated that HGF is a potential angiogenic growth factor in in vitro culture systems, there is no direct in vivo evidence for the angiogenic activity of HGF in physiological conditions. In this study, we hypothesized that transfection of HGF gene into infarcted myocardium could induce angiogenesis, potentially resulting in a beneficial response to hypoxia. Human HGF gene or control vector driven by the SRalpha promoter was transfected into rat myocardium by the HVJ-liposome method. Four days after in vivo transfection of human HGF gene, there was a marked increase in human immunoreactive HGF as compared with control vector (P < 0.01). In myocardium transfected with HGF vector, a significant increase in PCNA-positive endothelial cells was observed, while few PCNA-positive endothelial cells were detected in both control-vector-transfected and untreated myocardium. The number of vessels around the HGF injection sites was significantly increased as compared with control vector or vehicle (P < 0.01). Angiogenic activity induced by the transfection of HGF vector was also confirmed by the activation of a transcription factor, ets, which is essential for angiogenesis. Furthermore, we studied the pathophysiological role of HGF in a myocardial infarction model. The concentration of endogenous HGF was significantly decreased in infarcted myocardium. Therefore, we hypothesized that transfection of HGF gene into infarcted myocardium could induce a beneficial response to the decreased endogenous HGF. Indeed, transfection of human HGF into infarcted myocardium also resulted in a significant increase in the number of vessels (P < 0. 01), accompanied by marked induction of ets binding activity and a significant increase in blood flow. Overall, the present results provide direct in vivo evidence for the induction of angiogenesis by transfection of the human HGF gene in rat non-infarcted and infarcted myocardium. The constant production of local HGF resulting from the transgene may be considered as an innovative therapeutic angiogenesis strategy for ischemic diseases such as myocardial infarction. Gene Therapy (2000) 7, 417-427.
Aoki
M
M
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.
Morishita
R
R
Taniyama
Y
Y
Kida
I
I
Moriguchi
A
A
Matsumoto
K
K
Nakamura
T
T
Kaneda
Y
Y
Higaki
J
J
Ogihara
T
T
D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D009203:Myocardial Infarction / Q000378:metabolism / Q000628:therapy*; D018919:Neovascularization, Physiologic; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018108:Respirovirus / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology; D014162:Transfection / Q000235:genetics; D015854:Up-Regulation
D018809:Proliferating Cell Nuclear Antigen; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor