Angiopoietin-1 promotes functional neovascularization that relieves ischemia by improving regional reperfusion in a swine chronic myocardial ischemia model.
This study investigates the long-term angiogenic effects of ANG-1 and VEGF in a swine chronic myocardial ischemia model. Four-weeks after gradual occlusion of the left circumflex coronary artery by ameroid constrictor, animals were injected with recombinant adenoviral vectors carrying either human ANG-1 (n=9), human VEGF(165) (n=10) or empty vector (n=7) into the left ventricle free wall supplied by the constricted artery. Left ventricular perfusion in animals that received AdANG-1 (3.25+/-0.16 ml/min/g, p<0.05) recovered robustly 4 weeks after gene transfer while ischemia persisted in the AdVEGF (1.09+/-0.13 ml/min/g) and empty vector (1.20+/-0.03 ml/min/g) groups. Microvascular densities in the left ventricles of animals that received AdANG-1 (19.61+/-1.76/0.572 mm(2) myocardial tissue, p<0.05) and AdVEGF (18.17+/-1.43/0.572 mm(2) myocardial tissue, p<0.05) were significantly higher than animals that received empty vector (13.53+/-0.92/0.572 mm(2) myocardial tissue) 12 weeks after gene transfer. ANG-1, but not VEGF, contributed to enhanced regional perfusion by increasing arteriolar density (1.9+/-0.4/0.572 mm(2) myocardial tissue vs. 0.7+/-0.2/0.572 mm(2) myocardial tissue, p<0.05) of large-sized (50-100 microm) arterioles. These data demonstrate that gene transfer of ANG-1 and VEGF enhances angiogenesis, but ANG-1 promotes sustained improvement of ventricular perfusion that expedites recovery of ischemic myocardium via arteriogenesis.
Shim
Winston S N
WS
Research and Development Unit, National Heart Center, 17 Third Hospital Avenue, Singapore 168752, Singapore. winston_shim_sn@nhc.com.sg
Li
Wei
W
Zhang
Li
L
Li
Shiqi
S
Ong
Hwee Choo
HC
Song
In-Chin
IC
Bapna
Akanksha
A
Ge
Ruowen
R
Lim
Yean Teng
YT
Chuah
Seng Chye
SC
Sim
Eugene K W
EK
Wong
Philip
P
D000256:Adenoviridae; D000704:Analysis of Variance; D042683:Angiopoietin-1 / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D017023:Coronary Angiography; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000033:anatomy & histology / Q000187:drug effects; D017931:DNA Primers; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000628:therapy*; D015425:Myocardial Reperfusion; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D012039:Regional Blood Flow; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology*
D042683:Angiopoietin-1; D017931:DNA Primers; D042461:Vascular Endothelial Growth Factor A