Adeno-associated viral vector-mediated vascular endothelial growth factor gene transfer induces neovascular formation in ischemic heart

被引:130
作者
Su, H
Lu, R
Kan, YW
机构
[1] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA
关键词
D O I
10.1073/pnas.250488097
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Vascular endothelial growth factor (VEGF) plays important roles in physiological and pathological angiogenesis. Recent studies have demonstrated that direct injection of VEGF protein, plasmid DNA, or an adenoviral vector encoding the VEGF gene into ischemic myocardium or limb can induce collateral blood Vessel formation and improve perfusion of the ischemic areas. However, these approaches have limitations ranging from a short-lasting effect to angioma formation. In this study, we investigated the feasibility of using adeno-associated viral (AAV) vectors to deliver VEGF genes to mouse myocardium. A cytomegalovirus promoter was used to drive genes for a human VEGF isoform, VEGF(165), and LacZ. A mouse myocardial ischemic model was generated by ligation of the anterior descending coronary artery. Approximately 10(11) copies of the AAV-VEGF vector mixed with 10(10) copies of AAV-LacZ were injected to one site of normal myocardium and a total of 10(10) copies of AAV-VEGF were injected to multiple sites of myocardium around the ischemic region. LacZ gene expression was observed up to 3 months after the Vector inoculation. After AAV-VEGF inoculation, neoangiogenesis was observed in the ischemic heart model but not in normal heart tissue. An inflammatory-cell infiltration was not observed in the AAV-VEGF- and AAV-LacZ-inoculated hearts, and angioma-like structure was not observed. These results indicated that injection of the AAV vector directly to myocardium could mediate efficient gene transfer and transgene expression and that VEGF gene delivered by AAV vector can induce angiogenesis in ischemic myocardium.
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页码:13801 / 13806
页数:6
相关论文
共 64 条
[51]  
Takeshita S, 1996, LAB INVEST, V75, P487
[52]  
TAKESHITA S, 1994, CIRCULATION, V90, P228
[53]   THERAPEUTIC ANGIOGENESIS - A SINGLE INTRAARTERIAL BOLUS OF VASCULAR ENDOTHELIAL GROWTH-FACTOR AUGMENTS REVASCULARIZATION IN A RABBIT ISCHEMIC HIND-LIMB MODEL [J].
TAKESHITA, S ;
ZHENG, LP ;
BROGI, E ;
KEARNEY, M ;
PU, LQ ;
BUNTING, S ;
FERRARA, N ;
SYMES, JF ;
ISNER, JM .
JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (02) :662-670
[54]  
TISCHER E, 1991, J BIOL CHEM, V266, P11947
[55]   Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion [J].
Tsurumi, Y ;
Takeshita, S ;
Chen, DF ;
Kearney, M ;
Rossow, ST ;
Passeri, J ;
Horowitz, JR ;
Symes, JF ;
Isner, JM .
CIRCULATION, 1996, 94 (12) :3281-3290
[56]  
Tsurumi Y, 1997, CIRCULATION, V96, P382
[57]   Left ventricular electromechanical mapping to assess efficacy of phVEGP165 gene transfer for therapeutic angiogenesis in chronic myocardial ischemia [J].
Vale, PR ;
Losordo, DW ;
Milliken, CE ;
Maysky, M ;
Esakof, DD ;
Symes, JF ;
Isner, JM .
CIRCULATION, 2000, 102 (09) :965-974
[58]  
Verrier ED, 2000, ANN THORAC SURG, V69, P23
[59]   Structure of adeno-associated virus vector DNA following transduction of the skeletal muscle [J].
Vincent-Lacaze, N ;
Snyder, RO ;
Gluzman, R ;
Bohl, D ;
Lagarde, C ;
Danos, O .
JOURNAL OF VIROLOGY, 1999, 73 (03) :1949-1955
[60]   PURIFICATION AND CHARACTERIZATION OF HYPOXIA-INDUCIBLE FACTOR-1 [J].
WANG, GL ;
SEMENZA, GL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (03) :1230-1237