Direct intramuscular injection of plasmid DNA encoding angiopoietin-1 but not angiopoietin-2 augments revascularization in the rabbit ischemic hindlimb

被引:166
作者
Shyu, KG
Manor, O
Magner, M
Yancopoulos, GD
Isner, JM
机构
[1] Tufts Univ, Sch Med, St Elizabeths Med Ctr, Dept Med Cardiol, Boston, MA 02135 USA
[2] Tufts Univ, Sch Med, St Elizabeths Med Ctr, Dept Biomed Res, Boston, MA 02135 USA
[3] Regeneron Pharmaceut Inc, Tarrytown, NY USA
关键词
growth substances; genes; collateral circulation; peripheral vascular disease; angiogenesis;
D O I
10.1161/01.CIR.98.19.2081
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background-Angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) have recently been identified as ligands for the endothelial cell-specific Tie2 receptor. Little is known regarding the impact of these Tie2 ligands on postnatal neovascularization. Accordingly, we tested the hypothesis that gene transfer of plasmid DNA encoding Ang1 and Ang2 could modulate collateral vessel development in a rabbit model of hindlimb ischemia. Methods and Resultsts-pAng1* (n=15), pJFE control (no Ang1* insert) (n=9), pAng2 (n=9), pcDNA3 control (no Ang2 insert) (n=10), or saline (n=5) was injected intramuscularly into the rabbit ischemic hindlimb, Collateral vessel development and limb perfusion were assessed before and 30 days after treatment. Calf blood pressure ratio (ischemic to normal hindlimb) was increased 30 days after Ang1* gene transfer versus controls (Ang1*, 0.90+/-0.02; pJFE, 0.76+/-0.05; saline, 0.77+/-0.03; P<0.05). Angiographic score was higher (P<0.05) in the pAng1* group (0.63+/-0.02) than in the pJFE (0.51+/-0.03) or saline (0.52+/-0.02) group. Maximal (postpapaverine) blood flow in the ischemic limb was higher (P<0.05) after pAng1* (67.8+/-4.9 mL/min) than pJFE (51.2+/-4.4 mL/min) or saline (52.9+/-4.9 mL/min). Capillary density and capillary/muscle fiber ratio (242+/-12/mm(2) and 0.89+/-0.06, respectively) were higher (P<0.01) with pAng1* than pJFE (172+/-11/mm(2) and 0.64+/-0.05) or saline (166+/-10/mm(2) and 0.67+/-0.05). Neovascularization was not enhanced with pAng2. Conclusions-Ang1 but not Ang2 gene transfer produces anatomic and physiological evidence of enhanced collateral vessel formation. Ang1 may modulate neovascularization in adult animals and thus represents a feasible therapeutic strategy for patients with tissue ischemia. The role of Ang2 in postnatal neovascularization remains to be clarified.
引用
收藏
页码:2081 / 2087
页数:7
相关论文
共 44 条
[21]   GENE-THERAPY BY INTRAMUSCULAR INJECTION OF PLASMID DNA - STUDIES ON FIREFLY LUCIFERASE GENE-EXPRESSION IN MICE [J].
MANTHORPE, M ;
CORNEFERTJENSEN, F ;
HARTIKKA, J ;
FELGNER, J ;
RUNDELL, A ;
MARGALITH, M ;
DWARKI, V .
HUMAN GENE THERAPY, 1993, 4 (04) :419-431
[22]   ENDOTHELIAL RECEPTOR TYROSINE KINASES INVOLVED IN ANGIOGENESIS [J].
MUSTONEN, T ;
ALITALO, K .
JOURNAL OF CELL BIOLOGY, 1995, 129 (04) :895-898
[23]   Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells [J].
Namiki, A ;
Brogi, E ;
Kearney, M ;
Kim, EA ;
Wu, TG ;
Couffinhal, T ;
Varticovski, L ;
Isner, JM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (52) :31189-31195
[24]   POTENT SYNERGISM BETWEEN VASCULAR ENDOTHELIAL GROWTH-FACTOR AND BASIC FIBROBLAST GROWTH-FACTOR IN THE INDUCTION OF ANGIOGENESIS INVITRO [J].
PEPPER, MS ;
FERRARA, N ;
ORCI, L ;
MONTESANO, R .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1992, 189 (02) :824-831
[25]   ENHANCED REVASCULARIZATION OF THE ISCHEMIC LIMB BY ANGIOGENIC THERAPY [J].
PU, LQ ;
SNIDERMAN, AD ;
BRASSARD, R ;
LACHAPELLE, KJ ;
GRAHAM, AM ;
LISBONA, R ;
SYMES, JF .
CIRCULATION, 1993, 88 (01) :208-215
[26]   THE RECEPTOR TYROSINE KINASE TIE IS REQUIRED FOR INTEGRITY AND SURVIVAL OF VASCULAR ENDOTHELIAL-CELLS [J].
PURI, MC ;
ROSSANT, J ;
ALITALO, K ;
BERNSTEIN, A ;
PARTANEN, J .
EMBO JOURNAL, 1995, 14 (23) :5884-5891
[27]   Mechanisms of angiogenesis [J].
Risau, W .
NATURE, 1997, 386 (6626) :671-674
[28]   TIE-1 AND TIE-2 DEFINE ANOTHER CLASS OF PUTATIVE RECEPTOR TYROSINE KINASE GENES EXPRESSED IN EARLY EMBRYONIC VASCULAR SYSTEM [J].
SATO, TN ;
QIN, Y ;
KOZAK, CA ;
AUDUS, KL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (20) :9355-9358
[29]   DISTINCT ROLES OF THE RECEPTOR TYROSINE KINASES TIE-1 AND TIE-2 IN BLOOD-VESSEL FORMATION [J].
SATO, TN ;
TOZAWA, Y ;
DEUTSCH, U ;
WOLBURGBUCHHOLZ, K ;
FUJIWARA, Y ;
GENDRONMAGUIRE, M ;
GRIDLEY, T ;
WOLBURG, H ;
RISAU, W ;
QIN, Y .
NATURE, 1995, 376 (6535) :70-74
[30]   FAILURE OF BLOOD-ISLAND FORMATION AND VASCULOGENESIS IN FLK-1-DEFICIENT MICE [J].
SHALABY, F ;
ROSSANT, J ;
YAMAGUCHI, TP ;
GERTSENSTEIN, M ;
WU, XF ;
BREITMAN, ML ;
SCHUH, AC .
NATURE, 1995, 376 (6535) :62-66