Abstract
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 SRĪ± 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hanania EG et al. Recent advances in the application of gene therapy to human disease Am J Med 1995 99: 537ā552
McGarrity GJ, Anderson WF . Human gene therapy protocols: RAC review Science 1995 268: 1261
Post LE . RAC's review of gene therapy: it's time to move on Hum Gene Ther 1994 5: 1311ā1312
Yanagisawa-Miwa A et al. Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor Science 1992 257: 1401ā1403
Harada K et al. Vascular endothelial growth factor administration in chronic myocardial ischemia Am J Physiol 1996 270: H1791āH1802
Aoki M et al. Efficient in vivo gene transfer into the heart in the rat myocardial infarction model using the HVJ (hemagglutinating virus of Japan)-liposome method J Mol Cell Cardiol 1997 29: 949ā959
Aoki M et al. Survival of grafts of genetically modified cardiac myocytes transfected with FITC-labeled oligodeoxynucleotides and the beta-galactosidase gene in the noninfarcted area, but not the myocardial infarcted area Gene Therapy 1997 4: 120ā127
Matsumoto K, Nakamura T . Hepatocyte growth factor (HGF) as tissue organizer for organogenesis and regeneration Biochem Biophys Res Commun 1997 239: 639ā644
Matsumoto K, Nakamura T . Emerging multipotent aspects of hepatocyte growth factor J Biochem Tokyo 1996 119: 591ā600
Bussolino F et al. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth J Cell Biol 1992 119: 629ā641
Nakamura Y et al. A vascular modulator, hepatocyte growth factor, is associated with systolic pressure Hypertension 1996 28: 409ā413
Hayashi S et al. Autocrine-paracrine effects of overexpression of hepatocyte growth factor gene on growth of endothelial cells Biochem Biophys Res Commun 1996 220: 539ā545
Nakamura Y et al. Hepatocyte growth factor is a novel member of the endothelium-specific growth factors: additive stimulatory effect of hepatocyte growth factor with basic fibroblast growth factor but not with vascular endothelial growth factor J Hypertens 1996 14: 1067ā1072
Silvagno F et al. In vivo activation of met tyrosine kinase by heterodimeric hepatocyte growth factor molecule promotes angiogenesis Arterioscler Thromb Vasc Biol 1995 15: 1857ā1865
Nakamura Y et al. Expression of local hepatocyte growth factor system in vascular tissues Biochem Biophys Res Commun 1995 215: 483ā488
Nicosia RF, Nicosia SV, Smith M . Vascular endothelial growth factor, platelet-derived growth factor, and insulin-like growth factor-1 promote rat aortic angiogenesis in vitro Am J Pathol 1994 145: 1023ā1029
Lewin B . Oncogenic conversion by regulatory changes in transcription factors Cell 1991 64: 303ā312
Risau W, Flamme I . Vasculogenesis Ann Rev Cell Dev Biol 1995 11: 73ā91
Iwasaka C, Tanaka K, Abe M, Sato Y . Ets-1 regulates angiogenesis by inducing the expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of vascular endothelial cells J Cell Physiol 1996 169: 522ā531
Maroulakou IG, Papas TS, Green JE . Differential expression of ets-1 and ets-2 proto-oncogenes during murine embryogenesis Oncogene 1994 9: 1551ā1565
Wasylyk B et al. The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation Nature 1990 346: 191ā193
Wasylyk C, Kerckaert JP, Wasylyk B . A novel modulator domain of Ets transcription factors Genes Dev 1992 6: 965ā974
Kola I et al. The Ets1 transcription factor is widely expressed during murine embryo development and is associated with mesodermal cells involved in morphogenetic processes such as organ formation Proc Natl Acad Sci USA 1993 90: 7588ā7592
Vandenbunder B et al. Complementary patterns of expression of c-ets 1, c-myb and c-myc in the blood-forming system of the chick embryo Development 1989 107: 265ā274
Vandenbunder B et al. Does the transcription factor c-ets1 take part in the regulation of angiogenesis and tumor invasion? Folia Biol Praha 1994 40: 301ā313
Nerlov C, Rorth P, Blasi F, Johnsen M . Essential AP-1 and PEA3 binding elements in the human urokinase enhancer display cell type-specific activity Oncogene 1991 6: 1583ā1592
Gum R et al. Stimulation of 92-kDa gelatinase B promoter activity by ras is mitogen-activated protein kinase kinase 1-independent and requires multiple transcription factor binding sites including closely spaced PEA3/ets and AP-1 sequences J Biol Chem 1996 271: 10672ā10680
Yo Y et al. Actions of hepatocyte growth factor as a local modulator in the kidney: potential role in pathogenesis of renal disease Kidney Int 1998 53: 50ā58
Liu Y, Michalopoulos GK, Zarnegar R . Structural and functional characterization of the mouse hepatocyte growth factor gene promoter J Biol Chem 1994 269: 4152ā4160
Stein I et al. Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes Mol Cell Biol 1995 15: 5363ā5368
Banai S et al. Upregulation of vascular endothelial growth factor expression induced by myocardial ischaemia: implications for coronary angiogenesis Cardiovasc Res 1994 8: 1176ā1179
Hashimoto E et al. Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart Am J Physiol 1994 267: H1948āH1954
Isner JM et al. Arterial gene transfer for therapeutic angiogenesis in patients with peripheral artery disease Hum Gene Ther 1996 7: 959ā988
Takeshita S et al. Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo Lab Invest 1996 75: 487ā501
Ono K et al. Enhanced expression of hepatocyte growth factor/c-Met by myocardial ischemia and reperfusion in a rat model Circulation 1997 95: 2552ā2558
Sobel B, Bresnahan G, Shell W, Yoder R . Estimation of infarct size in man and its relation to prognosis Circulation 1972 106: 640ā648
Ueda H et al. Gene transfection of hepatocyte growth factor attenuates reperfusion injury in the heart Ann Thorac Surg 1999 67: 1726ā1731
Yo Y et al. Potential role of hepatocyte growth factor in the maintenance of renal structure: anti-apoptotic action of HGF on epithelial cells Kidney Int 1998 54: 1128ā1138
Aoki M et al. In vivo transfer efficiency of antisense oligonucleotides into the myocardium using HVJ-liposome method Biochem Biophys Res Commun 1997 231: 540ā545
Nakamura T et al. Molecular cloning and expression of human hepatocyte growth factor Nature 1989 342: 440ā443
Seki T et al. Organization of the human hepatocyte growthfactor-encoding gene Gene 1991 102: 213ā219
Morishita R et al. Novel and effective gene transfer technique for study of vascular renin angiotensin system J Clin Invest 1993 91: 2580ā2585
Kaneda Y, Iwai K, Uchida T . Increased expression of DNA cointroduced with nuclear protein in adult rat liver Science 1989 243: 375ā378
Yamada A et al. Rapid and sensitive enzyme-linked immunosorbent assay for measurement of HGF in rat and human tissues Biomed Res 1995 16: 105ā114
Nakayama T et al. Expression of the Ets-1 proto-oncogene in human gastric carcinoma: correlation with tumor invasion Am J Pathol 1996 149: 1931ā1939
Morishita R et al. In vivo transfixion of cis element ādecoyā against NFkB binding site prevented myocardial infarction as gene therapy Nature Med 1997 3: 894ā899
Morishita R et al. A novel molecular strategy using cis element ādecoyā of E2F binding site inhibits smooth muscle proliferation in vivo Proc Natl Acad Sci USA 1995 92: 5855ā5859
Murohara T et al. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia J Clin Invest 1998 101: 2567ā2578
Couffinhal T et al. A mouse model of angiogenesis Am J Pathol 1998 152: 1667ā1679
Acknowledgements
We wish to thank Toshie Nata for their excellent technical assistance. This work was partially supported by grants from Japan Health Sciences Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Hoan-sya Foundation, the Japan Cardiovascular Research Foundation, a Japan Heart Foundation Research Grant, a Grant-in-Aid from The Tokyo Biochemical Research Foundation and a Grant-in-Aid from The Ministry of Education, Science, Sports and Culture.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Aoki, M., Morishita, R., Taniyama, Y. et al. Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets. Gene Ther 7, 417ā427 (2000). https://doi.org/10.1038/sj.gt.3301104
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3301104
Keywords
This article is cited by
-
Hepatocyte growth factor-modified hair follicle stem cells ameliorate cerebral ischemia/reperfusion injury in rats
Stem Cell Research & Therapy (2023)
-
Hepatocyte growth factor and carotid intima-media thickness in relation to circulating CD34-positive cell levels
Environmental Health and Preventive Medicine (2018)
-
Study on inflammation-related genes and microRNAs, with special emphasis on the vascular repair factor HGF and miR-574-3p, in monocytes and serum of patients with T2D
Diabetology & Metabolic Syndrome (2016)
-
Cross talk of the first-line defense TLRs with PI3K/Akt pathway, in preconditioning therapeutic approach
Molecular and Cellular Therapies (2015)
-
Adenovirus-mediated transfer of hepatocyte growth factor gene to human dental pulp stem cells under good manufacturing practice improves their potential for periodontal regeneration in swine
Stem Cell Research & Therapy (2015)