Plasmid-mediated vegf gene transfer induces cardiomyogenesis and reduces myocardial infarct size in sheep

Plasmid-mediated vegf gene transfer induces cardiomyogenesis and reduces myocardial infarct size in sheep


Play all audios:

Loading...

ABSTRACT We have recently reported that in pigs with chronic myocardial ischemia heart transfection with a plasmid encoding the 165 isoform of human vascular endothelial growth factor


(p_VEGF__165_) induces an increase in the mitotic index of adult cardiomyocytes and cardiomyocyte hyperplasia. On these bases we hypothesized that _VEGF_ gene transfer could also modify the


evolution of experimental myocardial infarct. In adult sheep p_VEGF__165_ (3.8 mg, _n_=7) or empty plasmid (_n_=7) was injected intramyocardially 1 h after coronary artery ligation. After 15


days infarct area was 11.3±1.3% of the left ventricle in the VEGF group and 18.2±2.1% in the empty plasmid group (_P_<0.02). The mechanisms involved in infarct size reduction (assessed


in additional sheep at 7 and 10 days after infarction) included an increase in early angiogenesis and arteriogenesis, a decrease in peri-infarct fibrosis, a decrease in myofibroblast


proliferation, enhanced cardiomyoblast proliferation and mitosis of adult cardiomyocytes with occasional cytokinesis. Resting myocardial perfusion (99mTc-sestamibi SPECT) was higher in


VEGF-treated group than in empty plasmid group 15 days after myocardial infarction. We conclude that plasmid-mediated _VEGF_ gene transfer reduces myocardial infarct size by a combination of


effects including neovascular proliferation, modification of fibrosis and cardiomyocyte regeneration. Access through your institution Buy or subscribe This is a preview of subscription


content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 6 print issues and online access $259.00 per year only $43.17 per issue


Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL


ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS LOW DOSE ADENOVIRAL VAMMIN GENE TRANSFER


INDUCES MYOCARDIAL ANGIOGENESIS AND INCREASES LEFT VENTRICULAR EJECTION FRACTION IN ISCHEMIC PORCINE HEART Article Open access 03 December 2024 AAV2-VEGF-B GENE THERAPY FAILED TO INDUCE


ANGIOGENESIS IN ISCHEMIC PORCINE MYOCARDIUM DUE TO INFLAMMATORY RESPONSES Article Open access 07 February 2022 SAFETY AND BIODISTRIBUTION OF XC001 (ENCOBERMINOGENE REZMADENOVEC) GENE THERAPY


IN RATS: A POTENTIAL THERAPY FOR CARDIOVASCULAR DISEASES Article 18 August 2023 REFERENCES * Laguens R, Cabeza Meckert P, Vera Janavel G, Del Valle H, Lascano E, Negroni J _et al_. Entrance


in mitosis of adult cardiomyocytes in ischemic pig hearts after plasmid-mediated rhVEGF165 gene transfer. _Gene Therapy_ 2002; 9: 1676–1681. Article  CAS  PubMed  Google Scholar  * Laguens


R, Cabeza Meckert P, Vera Janavel G, De Lorenzi A, Lascano E, Negroni J _et al_. Cardiomyocyte hyperplasia after plasmid-mediated vascular endothelial growth factor gene transfer in pigs


with chronic myocardial ischemia. _J Gene Med_ 2004; 6: 222–227. Article  CAS  PubMed  Google Scholar  * Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R _et al_. Evidence


that human cardiac myocytes divide after myocardial infarction. _N Engl J Med_ 2001; 344: 1750–1757. Article  CAS  PubMed  Google Scholar  * Anversa P, Kajstura J . Ventricular myocytes are


not terminally differentiated in the adult mammalian heart. _Circ Res_ 1998; 83: 1–14. Article  CAS  PubMed  Google Scholar  * Cabeza Meckert P, García Rivello H, Vigliano C, Gonzalez P,


Favaloro R, Laguens R . Endomitosis and polyploidization of myocardial cells in the periphery of human acute myocardial infarction. _Cardiovasc Res_ 2005; 67: 116–123. Article  Google


Scholar  * Lazarowski AJ, Garcia Rivello HJ, Vera Janavel GL, Cuniberti LA, Cabeza Meckert PM, Yannarelli GG _et al_. Cardiomyocytes of chronically ischemic pig hearts express the MDR-1


gene-encoded P-glycoprotein. _J Histochem Cytochem_ 2005; 53: 845–850. Article  CAS  PubMed  Google Scholar  * Ertl G, Frantz S . Wound model of myocardial infarction. _Am J Physiol Heart


Circ Physiol_ 2005; 288: H981–H983. Article  CAS  PubMed  Google Scholar  * Garlanda C, Dejana E . Heterogeneity of endothelial cells: specific markers. _Arterioscler Thromb Vasc Biol_ 1997;


17: 1193–1202. Article  CAS  PubMed  Google Scholar  * Yanagisawa-Miwa A, Uchida Y, Nakamura F, Tomaru T, Kido H, Kamijo T _et al_. Salvage of infarcted myocardium by angiogenic action of


basic fibroblast growth factor. _Science_ 1992; 257: 1401–1403. Article  CAS  PubMed  Google Scholar  * Hariawala MD, Horowitz JR, Esakof D, Sheriff DD, Walter DH, Keyt B _et al_. VEGF


improves myocardial blood flow but produces EDRF-mediated hypotension in porcine hearts. _J Surg Res_ 1996; 63: 77–82. Article  CAS  PubMed  Google Scholar  * Goncalves LM . Angiogenic


growth factors: potential new treatment for acute myocardial infarction? _Cardiovasc Res_ 2000; 45: 294–302. Article  CAS  PubMed  Google Scholar  * Shyu KG, Wang MT, Wang BW, Chang CC, Leu


JG, Kuan P _et al_. Intramyocardial injection of naked DNA encoding HIF-1alpha/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. _Cardiovasc Res_ 2002;


54: 576–583. Article  CAS  PubMed  Google Scholar  * Takahashi K, Ito Y, Morikawa M, Kobune M, Huang J, Tsukamoto M _et al_. Adenoviral-delivered angiopoietin-1 reduces the infarction and


attenuates the progression of cardiac dysfunction in the rat model of acute myocardial infarction. _Mol Ther_ 2003; 8: 584–592. Article  CAS  PubMed  Google Scholar  * Siddiqui AJ, Blomberg


P, Wardell E, Hellgren I, Eskandarpour M, Islam KB _et al_. Combination of angiopoietin-1 and vascular endothelial growth factor gene therapy enhances arteriogenesis in the ischemic


myocardium. _Biochem Biophys Res Commun_ 2003; 310: 1002–1009. Article  CAS  PubMed  Google Scholar  * Hao X, Mansson-Broberg A, Blomberg P, Dellgren G, Siddiqui AJ, Grinnemo KH _et al_.


Angiogenic and cardiac functional effects of dual gene transfer of VEGF-A165 and PDGF-BB after myocardial infarction. _Biochem Biophys Res Commun_ 2004; 322: 292–296. Article  CAS  PubMed 


Google Scholar  * Su H, Joho S, Huang Y, Barcena A, Arakawa-Hoyt J, Grossman W _et al_. Adeno-associated viral vector delivers cardiac-specific and hypoxia-inducible VEGF expression in


ischemic mouse hearts. _Proc Natl Acad Sci USA_ 2004; 101: 16280–16285. Article  CAS  PubMed  PubMed Central  Google Scholar  * Okada H, Takemura G, Kosai K, Li Y, Takahashi T, Esaki M _et


al_. Postinfarction gene therapy against transforming growth factor-beta signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure. _Circulation_


2005; 111: 2430–2437. Article  CAS  PubMed  Google Scholar  * Li W, Tanaka K, Ihaya A, Fujibayashi Y, Takamatsu S, Morioka K _et al_. Gene therapy for chronic myocardial ischemia using


platelet-derived endothelial cell growth factor in dogs. _Am J Physiol Heart Circ Physiol_ 2005; 288: H408–H415. Article  CAS  PubMed  Google Scholar  * Funatsu T, Sawa Y, Ohtake S,


Takahashi T, Matsumiya G, Matsuura N _et al_. Therapeutic angiogenesis in the ischemic canine heart induced by myocardial injection of naked complementary DNA plasmid encoding hepatocyte


growth factor. _J Thorac Cardiovasc Surg_ 2002; 124: 1099–1105. Article  CAS  PubMed  Google Scholar  * Olivetti G, Cigola E, Maestri R, Corradi D, Lagrasta C, Gambert SR _et al_. Aging,


cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart. _J Mol Cell Cardiol_ 1996; 28: 1463–1477.


Article  CAS  PubMed  Google Scholar  * Markovitz LJ, Savage EB, Ratcliffe MB, Bavaria JE, Kreiner G, Iozzo RV _et al_. Large animal model of left ventricular aneurysm. _Ann Thorac Surg_


1989; 48: 838–845. Article  CAS  PubMed  Google Scholar  * Swynghedauw B . Molecular mechanisms of myocardial remodeling. _Physiol Rev_ 1999; 79: 215–262. Article  CAS  PubMed  Google


Scholar  * Sutton MG, Sharpe N . Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. _Circulation_ 2000; 101: 2981–2988. Article  CAS  PubMed  Google


Scholar  * Jackson BM, Gorman JH, Moainie SL, Guy TS, Narula N, Narula J _et al_. Extension of borderzone myocardium in postinfarction dilated cardiomyopathy. _J Am Coll Cardiol_ 2002; 40:


1160–1171. Article  PubMed  Google Scholar  * Crottogini A, Cabeza Meckert P, Vera Janavel G, Lascano E, Negroni J, Del Valle H _et al_. Arteriogenesis induced by intramyocardial vascular


endothelial growth factor 165 gene transfer in chronically ischemic pigs. _Hum Gene Ther_ 2003; 14: 1307–1318. Article  CAS  PubMed  Google Scholar  * Giordano FJ, Gerber HP, Williams SP,


VanBruggen N, Bunting S, Ruiz-Lozano P _et al_. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. _Proc Natl Acad Sci USA_


2001; 98: 5780–5785. Article  CAS  PubMed  PubMed Central  Google Scholar  * Kastrati A, Mehilli J, Nekolla S, Bollwein H, Martinoff S, Pache J, _et al_. STOPAMI-3 Study Investigators. A


randomized trial comparing myocardial salvage achieved by coronary stenting versus balloon angioplasty in patients with acute myocardial infarction considered ineligible for reperfusion


therapy. _J Am Coll Cardiol_ 2004; 43: 734–741. Article  PubMed  Google Scholar  * Kim YG, Suga SI, Kang DH, Jefferson JA, Mazzali M, Gordon KL _et al_. Vascular endothelial growth factor


accelerates renal recovery in experimental thrombotic microangiopathy. _Kidney Int_ 2000; 58: 2390–2399. Article  CAS  PubMed  Google Scholar  * Kang DH, Hughes J, Mazzali M, Schreiner GF,


Johnson RJ . Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. _J Am Soc Nephrol_


2001; 12: 1448–1457. CAS  PubMed  Google Scholar  * Deodato B, Arsic N, Zentilin L, Galeano M, Santoro D, Torre V _et al_. Recombinant AAV vector encoding human VEGF165 enhances wound


healing. _Gene Therapy_ 2002; 9: 777–785. Article  CAS  PubMed  Google Scholar  * Romano Di Peppe S, Mangoni A, Zambruno G, Spinetti G, Melillo G, Napolitano M _et al_. Adenovirus-mediated


VEGF165 gene transfer enhances wound healing by promoting angiogenesis in CD1 diabetic mice. _Gene Therapy_ 2002; 9: 1271–1277. Article  CAS  PubMed  Google Scholar  * Oh H, Bradfute SB,


Gallardo TD, Nakamura T, Gaussin V, Mishina Y _et al_. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. _Proc Natl Acad Sci USA_ 2003;


100: 12313–12318. Article  CAS  PubMed  PubMed Central  Google Scholar  * Rosenblatt-Velin N, Lepore MG, Cartoni C, Beermann F, Pedrazzini T . FGF-2 controls the differentiation of resident


cardiac precursors into functional cardiomyocytes. _J Clin Invest_ 2005; 115: 1724–1733. Article  CAS  PubMed  PubMed Central  Google Scholar  * Beltrami AP, Barlucchi L, Torella D, Baker M,


Limana F, Chimenti S _et al_. Adult cardiac stem cells are multipotent and support myocardial regeneration. _Cell_ 2003; 114: 763–776. Article  CAS  PubMed  Google Scholar  * Dawn B, Stein


AB, Urbanek K, Rota M, Whang B, Rastaldo R _et al_. Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function.


_Proc Natl Acad Sci USA_ 2005; 102: 3766–3771. Article  CAS  PubMed  PubMed Central  Google Scholar  * Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J _et al_.


Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. _Nat Med_ 2001; 7:


430–436. Article  CAS  PubMed  Google Scholar  * Schuster MD, Kocher AA, Seki T, Martens TP, Xiang G, Homma S _et al_. Myocardial neovascularization by bone marrow angioblasts results in


cardiomyocyte regeneration. _Am J Physiol Heart Circ Physiol_ 2004; 287: H525–H532. Article  CAS  PubMed  Google Scholar  * Suzuki K, Murtuza B, Smolenski RT, Sammut IA, Suzuki N, Kaneda Y


_et al_. Cell transplantation for the treatment of acute myocardial infarction using vascular endothelial growth factor-expressing skeletal myoblasts. _Circulation_ 2001; 104: I-207–I-212.


Article  CAS  Google Scholar  * Duda DG, Jain RK . Pleiotropy of tissue-specific growth factors: from neurons to vessels via the bone marrow. _J Clin Invest_ 2005; 115: 596–598. Article  CAS


  PubMed  PubMed Central  Google Scholar  * Suzuki G, Lee T-C, Fallavollita JA, Canty Jr JM . Adenoviral gene transfer of FGF-5 to hibernating myocardium improves function and stimulates


myocytes to hypertrophy and reenter the cell cycle. _Circ Res_ 2005; 96: 767–775. Article  CAS  PubMed  Google Scholar  * Couffinhal T, Silver M, Zheng LP, Kearney M, Witzenbichler B, Isner


JM . Mouse model of angiogenesis. _Am J Pathol_ 1998; 152: 1667–1779. CAS  PubMed  PubMed Central  Google Scholar  * Ferrara N, Gerber HP, LeCouter J . The biology of VEGF and its receptors.


_Nat Med_ 2003; 9: 669–676. Article  CAS  PubMed  Google Scholar  * Hachamovitch R, Berman DS, Kiat H, Cohen I, Cabico JA, Friedman J _et al_. Exercise myocardial perfusion SPECT in


patients without known coronary artery disease: incremental prognostic value and use in risk stratification. _Circulation_ 1996; 93: 905–914. Article  CAS  PubMed  Google Scholar  * Feng B,


Sitek A, Gullberg GT . Calculation of the left ventricular ejection fraction without edge detection: application to small hearts. _J Nucl Med_ 2002; 43: 786–794. PubMed  Google Scholar 


Download references ACKNOWLEDGEMENTS This work was supported by grants from The René G Favaloro University Foundation and by grant PID #268 from the Argentine National Agency for Scientific


and Technological Promotion (ANPCyT), Secretariat for Technology, Science and Productive Innovation (SeTCIP). Drs Crottogini and Laguens are established Investigators of National Council for


Scientific and Technical Investigations (CONICET). We thank technicians Julio Martínez, Fabián Gauna and Marcela Álvarez, veterinarians María Besansón, Pedro Iguain and Marta Tealdo and


animal house personnel Juan Ocampo, Osvaldo Sosa and Juan Mansilla. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Physiology, Favaloro University, Buenos Aires, Argentina G


Vera Janavel & A Crottogini * Department of Pathology, Favaloro University, Buenos Aires, Argentina P Cabeza Meckert, L Cuniberti & R Laguens * Scientific Investigation Commission


(CIC), Buenos Aires Province, Argentina P Cabeza Meckert * Institute of Cardiology and Cardiovascular Surgery of the Favaloro Foundation, Buenos Aires, Argentina A Mele * Bio Sidus, Buenos


Aires, Argentina M Papouchado, N Fernández, A Bercovich, M Criscuolo & C Melo Authors * G Vera Janavel View author publications You can also search for this author inPubMed Google


Scholar * A Crottogini View author publications You can also search for this author inPubMed Google Scholar * P Cabeza Meckert View author publications You can also search for this author


inPubMed Google Scholar * L Cuniberti View author publications You can also search for this author inPubMed Google Scholar * A Mele View author publications You can also search for this


author inPubMed Google Scholar * M Papouchado View author publications You can also search for this author inPubMed Google Scholar * N Fernández View author publications You can also search


for this author inPubMed Google Scholar * A Bercovich View author publications You can also search for this author inPubMed Google Scholar * M Criscuolo View author publications You can also


search for this author inPubMed Google Scholar * C Melo View author publications You can also search for this author inPubMed Google Scholar * R Laguens View author publications You can


also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to R Laguens. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE


Vera Janavel, G., Crottogini, A., Cabeza Meckert, P. _et al._ Plasmid-mediated VEGF gene transfer induces cardiomyogenesis and reduces myocardial infarct size in sheep. _Gene Ther_ 13,


1133–1142 (2006). https://doi.org/10.1038/sj.gt.3302708 Download citation * Received: 20 July 2005 * Revised: 17 November 2005 * Accepted: 18 November 2005 * Published: 06 April 2006 * Issue


Date: 01 August 2006 * DOI: https://doi.org/10.1038/sj.gt.3302708 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a


shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * myocardial infarction * VEGF *


heart regeneration * cardiomyocytes