Vascular wall maturation and prolonged angiogenic effect by endothelial-specific platelet-derived growth factor expression

被引:16
作者
Levanon, Keren
Varda-Bloom, Nira
Greenberger, Shoshana
Barshack, Iris
Goldberg, Iris
Orenstein, Arie
Breitbart, Eyal
Shaish, Aviv
Harats, Dror [1 ]
机构
[1] Chaim Sheba Med Ctr, Inst Lipid & Atherosclerosis Res, IL-52621 Tel Hashomer, Israel
[2] Chaim Sheba Med Ctr, Inst Pathol, IL-52621 Tel Hashomer, Israel
[3] Chaim Sheba Med Ctr, Adv Technol Inst, IL-52621 Tel Hashomer, Israel
[4] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel
[5] Vasc Biogen Ltd, Or Yehuda, Israel
关键词
angiogenesis-inducing agents; endothelin-1; endothelium; vascular; gene therapy; promoter regions; ischemia; vascular endothelial growth factor A; platelet-derived growth factor; adenovirus; murine model;
D O I
10.1159/000095561
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Background: The implementation of angiogenic gene therapy at clinics is hindered by the transience of the therapeutic effect. Recruiting vascular wall smooth muscle cells, a process termed 'maturation', can stabilize newly formed vessels. Objective: To induce angiogenesis followed by vessel maturation in a murine ischemic limb model by endothelial cell-specific promoter regulated expression of vascular endothelial growth factor ( VEGF) and platelet-derived growth factor-BB (PDGF-BB). Methods: We constructed adenoviral vectors containing angiogenic factors VEGF and PDGF-B regulated by a modified preproendothelin-1 (PPE-1-3x) promoter and investigated their angiogenic effect in a murine ischemic limb model. Results: VEGF gene therapy increased perfusion and the vessel density in the limb shortly after expression with PPE-1-3x promoter or cytomegalovirus (CMV) promoter vectors, but only PPE-1-3xVEGF treatment exhibited a sustained effect. Expression of PDGF-B by PPE-1-3x promoter resulted in morphological maturation of the vasculature and further increased the perfusion, while nonspecific expression of PDGF-B with CMV promoter had no therapeutic effect. Regulation of dual therapy with VEGF and PDGF-B by PPE-1-3x promoter resulted in an early-onset, sustained angiogenic effect accompanied by vessel maturation. Conclusions: Systemic gene therapy with the angiogenic factors VEGF and PDGF-B under angiogenic-endothelial cell-specific regulation was effective in inducing functionally and morphologically mature vasculature. Copyright (c) 2006 S. Karger AG, Basel.
引用
收藏
页码:149 / 158
页数:10
相关论文
共 43 条
[1]   VASCULAR ENDOTHELIAL GROWTH-FACTOR ACTS AS A SURVIVAL FACTOR FOR NEWLY FORMED RETINAL-VESSELS AND HAS IMPLICATIONS FOR RETINOPATHY OF PREMATURITY [J].
ALON, T ;
HEMO, I ;
ITIN, A ;
PEER, J ;
STONE, J ;
KESHET, E .
NATURE MEDICINE, 1995, 1 (10) :1024-1028
[2]  
Barleon B, 1997, CANCER RES, V57, P5421
[3]   PDGF-BB MODULATES ENDOTHELIAL PROLIFERATION AND ANGIOGENESIS IN-VITRO VIA PDGF BETA-RECEPTORS [J].
BATTEGAY, EJ ;
RUPP, J ;
IRUELAARISPE, L ;
SAGE, EH ;
PECH, M .
JOURNAL OF CELL BIOLOGY, 1994, 125 (04) :917-928
[4]   Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: Induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal [J].
Benjamin, LE ;
Keshet, E .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (16) :8761-8766
[5]   Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal [J].
Benjamin, LE ;
Golijanin, D ;
Itin, A ;
Pode, D ;
Keshet, E .
JOURNAL OF CLINICAL INVESTIGATION, 1999, 103 (02) :159-165
[6]  
Benjamin LE, 1998, DEVELOPMENT, V125, P1591
[7]   Developmental roles of platelet-derived growth factors [J].
Betsholtz, C ;
Karlsson, L ;
Lindahl, P .
BIOESSAYS, 2001, 23 (06) :494-507
[8]   Treatment of ischemic wounds using cultured dermal fibroblasts transduced retrovirally with PDGF-B and VEGF121 genes [J].
Breitbart, AS ;
Grande, DA ;
Laser, J ;
Barcia, M ;
Porti, D ;
Malhotra, S ;
Kogon, A ;
Grant, RT ;
Mason, JM .
ANNALS OF PLASTIC SURGERY, 2001, 46 (05) :555-561
[9]   Identification of an endothelial cell-specific regulatory region in the murine endothelin-1 gene [J].
Bu, X ;
Quertermous, T .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (51) :32613-32622
[10]   Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2 [J].
Cao, RH ;
Bråkenhielm, E ;
Pawliuk, R ;
Wariaro, D ;
Post, MJ ;
Wahlberg, E ;
Leboulch, P ;
Cao, YH .
NATURE MEDICINE, 2003, 9 (05) :604-613