Adenovirus-mediated expression of the secreted form of basic fibroblast growth factor (FGF-2) induces cellular proliferation and angiogenesis in vivo

被引:55
作者
Ueno, H
Li, JJ
Masuda, S
Qi, Z
Yamamoto, H
Takeshita, A
机构
[1] Molecular Cardiology Unit, Department of Cardiology, Kyushu University School of Medicine
[2] Department of Cardiology, Kyushu University, School of Medicine
关键词
adenovirus; gene therapy; angiogenesis; fibroblast growth factor; ischemic myocardium;
D O I
10.1161/01.ATV.17.11.2453
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Blood supply through collateral arteries is of critical importance in occlusive arterial diseases such as coronary atherosclerosis. Induction of angiogenic growth factor within either the narrowing arteries or jeopardized myocardium may promote angiogenesis in vivo, leading to salvage of ischemic myocardium. We constructed a replication-defective adenovirus (AdCAsFGF-2) coding for human basic fibroblast growth factor (FGF)-2 that is modified, so that its secretion will be facilitated, by tagging a signal sequence derived from FGF-4. A large quantity of FGF-2 was detected in both the cell lysate and culture medium of COS cells infected with AdCAsFGF-2, indicating that FGF-2 was secreted at least partly from the infected cells. The conditioned medium from the infected COS cells stimulated DNA synthesis in and induced cellular proliferation of arterial smooth muscle cells. These effects were eliminated by adenovirus-mediated overexpression of a dominant-negative truncated FGF-receptor type 1. Implantation of a gel of basement membrane proteins containing fibroblasts infected with AdCAsFGF-2 into the ventral subcutaneous space of mice induced extensive cellular proliferation and the formation of functional arterioles. Cells surrounding the vessels were positively immunostained with antibodies recognizing either smooth muscle-specific alpha-actin or factor VIII antigen as a marker for endothelium. These results suggest that AdCAsFGF-2 may be useful for delivering functional FGF-2 into tissues and may lead to therapeutic angiogenesis in vivo.
引用
收藏
页码:2453 / 2460
页数:8
相关论文
共 68 条
  • [21] MOLECULAR MECHANISMS OF ANGIOGENESIS - FIBROBLAST GROWTH-FACTOR SIGNAL-TRANSDUCTION
    FRIESEL, RE
    MACIAG, T
    [J]. FASEB JOURNAL, 1995, 9 (10) : 919 - 925
  • [22] BASIC FIBROBLAST GROWTH-FACTOR AND TRANSFORMING GROWTH-FACTOR-BETA-1 - SYNERGISTIC MEDIATORS OF ANGIOGENESIS IN-VITRO
    GAJDUSEK, CM
    LUO, ZG
    MAYBERG, MR
    [J]. JOURNAL OF CELLULAR PHYSIOLOGY, 1993, 157 (01) : 133 - 144
  • [23] GOTO F, 1993, LAB INVEST, V69, P508
  • [24] *GROUP TVCASCS, 1992, CIRCULATION, V86, P121
  • [25] EFFICIENT AND SELECTIVE ADENOVIRUS-MEDIATED GENE-TRANSFER INTO VASCULAR NEOINTIMA
    GUZMAN, PJ
    LEMARCHAND, P
    CRYSTAL, RG
    EPSTEIN, SE
    FINKEL, T
    [J]. CIRCULATION, 1993, 88 (06) : 2838 - 2848
  • [26] EFFICIENT GENE-TRANSFER INTO MYOCARDIUM BY DIRECT-INJECTION OF ADENOVIRUS VECTORS
    GUZMAN, RJ
    LEMARCHAND, P
    CRYSTAL, RG
    EPSTEIN, SE
    FINKEL, T
    [J]. CIRCULATION RESEARCH, 1993, 73 (06) : 1202 - 1207
  • [27] BASIC FIBROBLAST GROWTH-FACTOR IMPROVES MYOCARDIAL-FUNCTION IN CHRONICALLY ISCHEMIC PORCINE HEARTS
    HARADA, K
    GROSSMAN, W
    FRIEDMAN, M
    EDELMAN, ER
    PRASAD, PV
    KEIGHLEY, CS
    MANNING, WJ
    SELLKE, FW
    SIMONS, M
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1994, 94 (02) : 623 - 630
  • [28] JOHNSON DE, 1993, ADV CANCER RES, V60, P1
  • [29] BASIC FIBROBLAST GROWTH-FACTOR IN ATRIA AND VENTRICLES OF THE VERTEBRATE HEART
    KARDAMI, E
    FANDRICH, RR
    [J]. JOURNAL OF CELL BIOLOGY, 1989, 109 (04) : 1865 - 1875
  • [30] QUANTITATIVE-DETERMINATION OF ADENOVIRUS-MEDIATED GENE DELIVERY TO RAT CARDIAC MYOCYTES IN-VITRO AND IN-VIVO
    KASSEISLER, A
    FALCKPEDERSEN, E
    ALVIRA, M
    RIVERA, J
    BUTTRICK, PM
    WITTENBERG, BA
    CIPRIANI, L
    LEINWAND, LA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (24) : 11498 - 11502