(Circulation. 2000;102:898.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
VEGF Gene Delivery to Myocardium
Deleterious Effects of Unregulated Expression
From the Department of Medicine and the Cardiovascular Research Institute (R.J.L., R.S.) and the Department of Pathology (P.C.U.), University of California, San Francisco, and the Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, Calif (M.L.S., W.E.B.-B., H.M.B.).
Correspondence to Randall J. Lee, MD, PhD, Cardiac Electrophysiology, MU East Tower, Box 1354, 500 Parnassus Ave, San Francisco, CA 94143-1354. E-mail lee{at}ep4.ucsf.edu
Background—Vascular endothelial growth factor (VEGF) is being investigated for therapeutic angiogenesis in ischemic myocardium. Primarily, transient delivery systems have been tested. The goal of this study was to investigate the effects of continuous expression of VEGF in myocardium by use of myoblast-mediated delivery.
Methods and Results—Primary murine myoblasts (5x105 cells in 10 µL of PBS with 0.5% BSA) expressing both the murine VEGF gene and the ß-galactosidase (ß-gal) gene from a retroviral promoter were implanted in the ventricular wall of immunodeficient mice (n=11) via a subdiaphragmatic approach. Control immunodeficient mice (n=12) were injected with the same number of myoblasts expressing only the ß-gal gene. Between days 14 and 16, surviving mice were euthanized and the hearts processed for histology. In the experimental group, 11 of 11 mice demonstrated failure to thrive by day 13; 5 deaths occurred between days 8 and 15. There were no complications in the control mice. Histochemistry documented successful implantation of myoblasts (positive ß-gal reaction product) in 6 of 6 surviving experimental mice and 12 of 12 controls. Histology disclosed intramural vascular tumors resembling hemangiomas in the VEGF-myoblast–injected myocardium in 6 of 6 surviving mice. ß-Gal–expressing cells were present at the site of the vascular tumors. Immunohistochemistry localized abundant endothelial nitric oxide synthase and CD31 (platelet and endothelial cell adhesion molecule) within the lesion, consistent with the presence of endothelial cells.
Conclusions—In this model, unregulated continuous expression of VEGF is associated with (1) a high rate of failure to thrive/death and (2) formation of endothelial cell–derived intramural vascular tumors in the implantation site. These results underscore the importance of regulating VEGF expression for therapeutic angiogenesis.
Key Words: angiogenesis • genes • coronary disease
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 M. Ruel, R. A. Kelly, and F. W. Sellke Therapeutic Angiogenesis, Transmyocardial Laser Revascularization, and Cell Therapy Card. Surg. Adult, January 1, 2003; 2(2003): 715 - 750. [Full Text]
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T. Funatsu, Y. Sawa, S. Ohtake, T. Takahashi, G. Matsumiya, N. Matsuura, T. Nakamura, and H. Matsuda Therapeutic angiogenesis in the ischemic canine heart induced by myocardial injection of naked complementary DNA plasmid encoding hepatocyte growth factor J. Thorac. Cardiovasc. Surg., December 1, 2002; 124(6): 1099 - 1105. [Abstract] [Full Text]
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W. W. Spurbeck, C. Y. C. Ng, T. S. Strom, E. F. Vanin, and A. M. Davidoff Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model Blood, October 16, 2002; 100(9): 3361 - 3368. [Abstract] [Full Text] [PDF]
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 C. Ruhrberg, H. Gerhardt, M. Golding, R. Watson, S. Ioannidou, H. Fujisawa, C. Betsholtz, and D. T. Shima Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis Genes & Dev., October 15, 2002; 16(20): 2684 - 2698. [Abstract] [Full Text] [PDF]
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R. CAO, E. BRAKENHIELM, X. LI, K. PIETRAS, J. WIDENFALK, A. OSTMAN, U. ERIKSSON, and Y. CAO Angiogenesis stimulated by PDGF-CC, a novel member in the PDGF family, involves activation of PDGFR-{alpha}{alpha} and -{alpha}{beta} receptors FASEB J, October 1, 2002; 16(12): 1575 - 1583. [Abstract] [Full Text] [PDF]
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 A. Saaristo, T. Veikkola, T. Tammela, B. Enholm, M. J. Karkkainen, K. Pajusola, H. Bueler, S. Yla-Herttuala, and K. Alitalo Lymphangiogenic Gene Therapy With Minimal Blood Vascular Side Effects J. Exp. Med., September 16, 2002; 196(6): 719 - 730. [Abstract] [Full Text] [PDF]
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K. A. Horvath, J. Doukas, C.-Y. J. Lu, N. Belkind, R. Greene, G. F. Pierce, and D. A. Fullerton Myocardial functional recovery after fibroblast growth factor 2 gene therapy as assessed by echocardiography and magnetic resonance imaging Ann. Thorac. Surg., August 1, 2002; 74(2): 481 - 487. [Abstract] [Full Text] [PDF]
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H. Su, J. Arakawa-Hoyt, and Y. W. Kan Adeno-associated viral vector-mediated hypoxia response element-regulated gene expression in mouse ischemic heart model PNAS, July 9, 2002; 99(14): 9480 - 9485. [Abstract] [Full Text] [PDF]
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 A. Takahashi, Y. Kureishi, J. Yang, Z. Luo, K. Guo, D. Mukhopadhyay, Y. Ivashchenko, D. Branellec, and K. Walsh Myogenic Akt Signaling Regulates Blood Vessel Recruitment during Myofiber Growth Mol. Cell. Biol., July 1, 2002; 22(13): 4803 - 4814. [Abstract] [Full Text] [PDF]
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 B. S. Zuckerbraun and E. Tzeng Vascular Gene Therapy: A Reality of the 21st Century Arch Surg, July 1, 2002; 137(7): 854 - 861. [Abstract] [Full Text] [PDF]
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I. Masaki, Y. Yonemitsu, A. Yamashita, S. Sata, M. Tanii, K. Komori, K. Nakagawa, X. Hou, Y. Nagai, M. Hasegawa, et al. Angiogenic Gene Therapy for Experimental Critical Limb Ischemia: Acceleration of Limb Loss by Overexpression of Vascular Endothelial Growth Factor 165 but not of Fibroblast Growth Factor-2 Circ. Res., May 17, 2002; 90(9): 966 - 973. [Abstract] [Full Text] [PDF]
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P Menasche and M Desnos Cardiac reparation: fixing the heart with cells, new vessels and genes Eur. Heart J. Suppl., April 1, 2002; 4(suppl_D): D73 - D81. [Abstract] [PDF]
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J. B. Kearney, C. A. Ambler, K.-A. Monaco, N. Johnson, R. G. Rapoport, and V. L. Bautch Vascular endothelial growth factor receptor Flt-1 negatively regulates developmental blood vessel formation by modulating endothelial cell division Blood, April 1, 2002; 99(7): 2397 - 2407. [Abstract] [Full Text] [PDF]
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M. Shimpo, U. Ikeda, Y. Maeda, M. Takahashi, H. Miyashita, H. Mizukami, M. Urabe, A. Kume, T. Takizawa, M. Shibuya, et al. AAV-mediated VEGF gene transfer into skeletal muscle stimulates angiogenesis and improves blood flow in a rat hindlimb ischemia model Cardiovasc Res, March 1, 2002; 53(4): 993 - 1001. [Abstract] [Full Text] [PDF]
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 J.M. ARBEIT Quiescent Hypervascularity Mediated by Gain of HIF-1{alpha} Function Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 133 - 142. [Abstract] [PDF]
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 S. B. Freedman and J. M. Isner Therapeutic Angiogenesis for Coronary Artery Disease Ann Intern Med, January 1, 2002; 136(1): 54 - 71. [Abstract] [Full Text] [PDF]
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A. Abramsson, O. Berlin, H. Papayan, D. Paulin, M. Shani, and C. Betsholtz Analysis of Mural Cell Recruitment to Tumor Vessels Circulation, January 1, 2002; 105(1): 112 - 117. [Abstract] [Full Text] [PDF]
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H. Huwer, C. Welter, C. Ozbek, M. Seifert, U. Straub, P. Greilach, G. Kalweit, and H. Isringhaus Simultaneous surgical revascularization and angiogenic gene therapy in diffuse coronary artery disease Eur. J. Cardiothorac. Surg., December 1, 2001; 20(6): 1128 - 1134. [Abstract] [Full Text] [PDF]
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 R. Khurana, J. F. Martin, and I. Zachary Gene Therapy for Cardiovascular Disease: A Case for Cautious Optimism Hypertension, November 1, 2001; 38(5): 1210 - 1216. [Abstract] [Full Text] [PDF]
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R. K. Bruick and S. L. McKnight Building better vasculature Genes & Dev., October 1, 2001; 15(19): 2497 - 2502. [Full Text] [PDF]
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D. A. Elson, G. Thurston, L. E. Huang, D. G. Ginzinger, D. M. McDonald, R. S. Johnson, and J. M. Arbeit Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1{alpha} Genes & Dev., October 1, 2001; 15(19): 2520 - 2532. [Abstract] [Full Text] [PDF]
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K. Suzuki, B. Murtuza, R. T. Smolenski, I. A. Sammut, N. Suzuki, Y. Kaneda, and M. H. Yacoub Cell Transplantation for the Treatment of Acute Myocardial Infarction Using Vascular Endothelial Growth Factor-Expressing Skeletal Myoblasts Circulation, September 18, 2001; 104 (2009): I-207 - I-212. [Abstract] [Full Text] [PDF]
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K. Suzuki, B. Murtuza, N. Suzuki, R. T. Smolenski, and M. H. Yacoub Intracoronary Infusion of Skeletal Myoblasts Improves Cardiac Function in Doxorubicin-Induced Heart Failure Circulation, September 18, 2001; 104 (2009): I-213 - I-217. [Abstract] [Full Text] [PDF]
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J. M. Isner, P. R. Vale, J. F. Symes, and D. W. Losordo Assessment of Risks Associated With Cardiovascular Gene Therapy in Human Subjects Circ. Res., August 31, 2001; 89(5): 389 - 400. [Abstract] [Full Text] [PDF]
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Y. Lu, J. Shansky, M. Del Tatto, P. Ferland, X. Wang, and H. Vandenburgh Recombinant Vascular Endothelial Growth Factor Secreted From Tissue-Engineered Bioartificial Muscles Promotes Localized Angiogenesis Circulation, July 31, 2001; 104(5): 594 - 599. [Abstract] [Full Text] [PDF]
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S. A. Nicklin, P. N. Reynolds, M. J. Brosnan, S. J. White, D. T. Curiel, A. F. Dominiczak, and A. H. Baker Analysis of Cell-Specific Promoters for Viral Gene Therapy Targeted at the Vascular Endothelium Hypertension, July 1, 2001; 38(1): 65 - 70. [Abstract] [Full Text] [PDF]
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R. J Bing Myocardial ischemia and infarction: growth of ideas Cardiovasc Res, July 1, 2001; 51(1): 13 - 20. [Abstract] [Full Text] [PDF]
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F. L. Celletti, P. R. Hilfiker, P. Ghafouri, and M. D. Dake Effect of human recombinant vascular endothelial growth factor165 on progression of atherosclerotic plaque J. Am. Coll. Cardiol., June 15, 2001; 37(8): 2126 - 2130. [Abstract] [Full Text] [PDF]
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M. Yokoyama and T. Hirase Harmonic Interplay of Angiogenic Growth Factors in the Development of Coronary Blood Vessels Circ. Res., June 8, 2001; 88(11): 1099 - 1101. [Full Text] [PDF]
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