This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Campbell, A. I.M. Articles by Stewart, D. J. Search for Related Content PubMed PubMed Citation Articles by Campbell, A. I.M. Articles by Stewart, D. J. Related Collections Angiogenesis Apoptosis Pulmonary biology and circulation Pulmonary circulation and disease Gene therapy

(Circulation. 2001;104:2242.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Cell-Based Gene Transfer of Vascular Endothelial Growth Factor Attenuates Monocrotaline-Induced Pulmonary Hypertension

Andrew I.M. Campbell, MD; Yidan Zhao, MD, PhD; Reena Sandhu, PhD; Duncan J. Stewart, MD

From the Divisions of Cardiac Surgery (A.I.M.C.) and Cardiology (Y.Z., R.S., D.J.S.), University of Toronto, Terrence Donnelly Heart Centre, St Michael’s Hospital, Toronto, Ontario, Canada.

Correspondence to D.J. Stewart, St Michael’s Hospital, 30 Bond St, Toronto, Ontario, Canada M5B 1W8. E-mail stewartd{at}smh.toronto.on.ca

Background— Pulmonary arterial hypertension is characterized by increased pulmonary vascular resistance secondary to a decrease in the caliber and number of pulmonary vascular channels. We hypothesized that the targeted overexpression of an angiogenic factor within the lung would potentially minimize the development and progression of pulmonary arterial hypertension by preventing the loss of existing vessels or by inducing the development of new blood vessels within the lung.

Methods and Results— We used a cell-based method of gene transfer to the pulmonary microvasculature by delivering syngeneic smooth muscle cells overexpressing vascular endothelial growth factor (VEGF)-A to inbred Fisher 344 rats in which pulmonary hypertension was induced with the pulmonary endothelial toxin monocrotaline. Four weeks after simultaneous endothelial injury and cell-based gene transfer, right ventricular (RV) hypertension and RV and vascular hypertrophy were significantly decreased in the VEGF-treated animals. Four weeks after gene transfer, the plasmid VEGF transcript was still detectable in the pulmonary tissue of animals injected with VEGF-transfected cells, demonstrating survival of the transfected cells and persistent transgene expression. In addition, delay of cell-based gene transfer until after the development of pulmonary hypertension also resulted in a significant decrease in the progression of RV hypertension and hypertrophy.

Conclusions— These results indicate that cell-based VEGF gene transfer is an effective method of preventing the development and progression of pulmonary hypertension in the monocrotaline model and suggest a potential therapeutic role for angiogenic factors in the therapy of this devastating disease.

Key Words: angiogenesis • gene therapy • endothelium-derived factors • hypertension, pulmonary • remodeling

This article has been cited by other articles:

				N. El-Bizri, L. Wang, S. L. Merklinger, C. Guignabert, T. Desai, T. Urashima, A. Y. Sheikh, R. H. Knutsen, R. P. Mecham, Y. Mishina, et al. Smooth Muscle Protein 22{alpha}-Mediated Patchy Deletion of Bmpr1a Impairs Cardiac Contractility but Protects Against Pulmonary Vascular Remodeling Circ. Res., February 15, 2008; 102(3): 380 - 388. [Abstract] [Full Text] [PDF]

				M. E. van Albada, G. J. du Marchie Sarvaas, J. Koster, M. C. Houwertjes, R. M. F. Berger, and R. G. Schoemaker Effects of erythropoietin on advanced pulmonary vascular remodelling Eur. Respir. J., January 1, 2008; 31(1): 126 - 134. [Abstract] [Full Text] [PDF]

				A. P. Wong, A. E. Dutly, A. Sacher, H. Lee, D. M. Hwang, M. Liu, S. Keshavjee, J. Hu, and T. K. Waddell Targeted cell replacement with bone marrow cells for airway epithelial regeneration Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L740 - L752. [Abstract] [Full Text] [PDF]

				L. Liu, H. Liu, G. Visner, and B. S. Fletcher Sleeping Beauty-mediated eNOS gene therapy attenuates monocrotaline-induced pulmonary hypertension in rats FASEB J, December 1, 2006; 20(14): 2594 - 2596. [Abstract] [Full Text] [PDF]

				S. I. Said Mediators and modulators of pulmonary arterial hypertension Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L547 - L558. [Abstract] [Full Text] [PDF]

				Y. D. Zhao, D. W. Courtman, D. S. Ng, M. J. Robb, Y. P. Deng, J. Trogadis, R. N. N. Han, and D. J. Stewart Microvascular Regeneration in Established Pulmonary Hypertension by Angiogenic Gene Transfer Am. J. Respir. Cell Mol. Biol., August 1, 2006; 35(2): 182 - 189. [Abstract] [Full Text] [PDF]

				S. Kanki-Horimoto, H. Horimoto, S. Mieno, K. Kishida, F. Watanabe, E. Furuya, and T. Katsumata Implantation of Mesenchymal Stem Cells Overexpressing Endothelial Nitric Oxide Synthase Improves Right Ventricular Impairments Caused by Pulmonary Hypertension Circulation, July 4, 2006; 114(1_suppl): I-181 - I-185. [Abstract] [Full Text] [PDF]

				K. Teichert-Kuliszewska, M. J.B. Kutryk, M. A. Kuliszewski, G. Karoubi, D. W. Courtman, L. Zucco, J. Granton, and D. J. Stewart Bone Morphogenetic Protein Receptor-2 Signaling Promotes Pulmonary Arterial Endothelial Cell Survival: Implications for Loss-of-Function Mutations in the Pathogenesis of Pulmonary Hypertension Circ. Res., February 3, 2006; 98(2): 209 - 217. [Abstract] [Full Text] [PDF]

				N. F. Voelkel, R. W. Vandivier, and R. M. Tuder Vascular endothelial growth factor in the lung Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L209 - L221. [Abstract] [Full Text] [PDF]

				L. Kugathasan, A. E. Dutly, Y. D. Zhao, Y. Deng, M. J. Robb, S. Keshavjee, and D. J. Stewart Role of Angiopoietin-1 in Experimental and Human Pulmonary Arterial Hypertension Chest, December 1, 2005; 128(6_suppl): 633S - 642S. [Abstract] [Full Text] [PDF]

				M. Rabinovitch Cellular and Molecular Pathobiology of Pulmonary Hypertension Conference Summary Chest, December 1, 2005; 128(6_suppl): 642S - 646S. [Full Text] [PDF]

				M. Rabinovitch Cellular and Molecular Pathobiology of Pulmonary Hypertension Conference Summary Chest, December 1, 2005; 128(6_suppl): 642S - 646S. [Full Text] [PDF]

				Y. D. Zhao, D. W. Courtman, Y. Deng, L. Kugathasan, Q. Zhang, and D. J. Stewart Rescue of Monocrotaline-Induced Pulmonary Arterial Hypertension Using Bone Marrow-Derived Endothelial-Like Progenitor Cells: Efficacy of Combined Cell and eNOS Gene Therapy in Established Disease Circ. Res., March 4, 2005; 96(4): 442 - 450. [Abstract] [Full Text] [PDF]

				A J Knox, J Stocks, and A Sutcliffe Angiogenesis and vascular endothelial growth factor in COPD Thorax, February 1, 2005; 60(2): 88 - 89. [Full Text] [PDF]

				T. Itoh, N. Nagaya, S. Murakami, T. Fujii, T. Iwase, H. Ishibashi-Ueda, C. Yutani, M. Yamagishi, H. Kimura, and K. Kangawa C-type Natriuretic Peptide Ameliorates Monocrotaline-induced Pulmonary Hypertension in Rats Am. J. Respir. Crit. Care Med., December 1, 2004; 170(11): 1204 - 1211. [Abstract] [Full Text] [PDF]

				N. Hattan, D. Warltier, W. Gu, C. Kolz, W. M. Chilian, and D. Weihrauch Autologous vascular smooth muscle cell-based myocardial gene therapy to induce coronary collateral growth Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H488 - H493. [Abstract] [Full Text] [PDF]

				M. Humbert, N. W. Morrell, S. L. Archer, K. R. Stenmark, M. R. MacLean, I. M. Lang, B. W. Christman, E. K. Weir, O. Eickelberg, N. F. Voelkel, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 13S - 24S. [Abstract] [Full Text] [PDF]

				D. J. Stewart, Y. D. Zhao, D. W. Courtman, N. Nagaya, T. Horio, K. Miyatake, Y. Chiba, K. Kangawa, M. Kanda, J. Hino, et al. Cell Therapy for Pulmonary Hypertension: What Is the True Potential of Endothelial Progenitor Cells? * Response Circulation, March 30, 2004; 109(12): e172 - e173. [Full Text] [PDF]

				M. Yoshida, Y. Iwasaki, M. Asai, T. Nigawara, and Y. Oiso Gene Therapy for Central Diabetes Insipidus: Effective Antidiuresis by Muscle-Targeted Gene Transfer Endocrinology, January 1, 2004; 145(1): 261 - 268. [Abstract] [Full Text] [PDF]

				Y. D. Zhao, A. I.M. Campbell, M. Robb, D. Ng, and D. J. Stewart Protective Role of Angiopoietin-1 in Experimental Pulmonary Hypertension Circ. Res., May 16, 2003; 92(9): 984 - 991. [Abstract] [Full Text] [PDF]

				R. Budhiraja and P. M. Hassoun Portopulmonary Hypertension: A Tale of Two Circulations Chest, February 1, 2003; 123(2): 562 - 576. [Abstract] [Full Text] [PDF]

				M. Fujita, R. J. Mason, C. Cool, J. M. Shannon, N. Hara, and K. A. Fagan Pulmonary hypertension in TNF-alpha -overexpressing mice is associated with decreased VEGF gene expression J Appl Physiol, December 1, 2002; 93(6): 2162 - 2170. [Abstract] [Full Text] [PDF]

				T. D. Le Cras, N. E. Markham, R. M. Tuder, N. F. Voelkel, and S. H. Abman Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure Am J Physiol Lung Cell Mol Physiol, September 1, 2002; 283(3): L555 - L562. [Abstract] [Full Text] [PDF]

				S. Babaei and D. J Stewart Overexpression of endothelial NO synthase induces angiogenesis in a co-culture model Cardiovasc Res, July 1, 2002; 55(1): 190 - 200. [Abstract] [Full Text] [PDF]

				M. M. Hoeper, N. Galie, G. Simonneau, and L. J. Rubin New Treatments for Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., May 1, 2002; 165(9): 1209 - 1216. [Full Text] [PDF]