Structural stability of neoangiogenic intramyocardial microvessels supports functional recovery in chronic ischemic myocardium.
We hypothesize that combining angiopoietin-1 (ANG-1) or ANG-2 with vascular endothelial growth factor (VEGF) improves myocardial perfusion and contractile function by modulating vascular adaptation of neoangiogenic microvessels in a chronic ischemic swine model. Four weeks after occlusion of the left circumflex coronary artery (LCx), animals were injected with AdVEGF(165) (n=6), AdVEGF(165)+AdANG-1 (n=6), AdVEGF(165)+AdANG-2 (n=6) or control vector (n=5) into the left ventricular posterolateral wall. Regional perfusion by fluorescent microspheres and segmental myocardial tissue velocity by tissue Doppler imaging (TDI) were assessed at baseline, 4 weeks post occlusion and 4 weeks post therapy. Despite similar vascular growth following VEGF+ANG-1 and VEGF+ANG-2 treatments, transmural myocardial contractility improved only when VEGF was paired with ANG-1. In contrast, regional systolic function deteriorated uniformly across subepicardial, mid-myocardial and subendocardial segments in VEGF and VEGF+ANG-2 treated groups. Contractile improvement was associated with enhanced vascular stability through augmented arteriole formation, tight structural integration between VE-cadherin and beta-catenin at endothelial junctions and improved cross-talk between endothelium and myocardium. Structural stability of developing intramyocardial microvessels contributes to systolic function during ischemic neovascularization. Coordinated regulation of angiogenic revascularization that supports vascular stability is a key aspect in improving therapeutic outcomes in ischemic myocardium.
Shim
Winston S N
WS
Research and Development Unit, National Heart Center, Singapore. Winston_SHIM_SN@nhc.com.sg
Lim
Sze Yun
SY
Li
Shi Qi
SQ
Gu
Yacui
Y
Ong
Hwee Choo
HC
Song
In Chin
IC
Chuah
Seng Chye
SC
Wong
Philip
P
D000256:Adenoviridae; D042683:Angiopoietin-1 / Q000096:biosynthesis* / Q000235:genetics; D042702:Angiopoietin-2 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001160:Arterioles / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002908:Chronic Disease; D003326:Coronary Circulation / Q000235:genetics; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D004727:Endothelium / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D008297:Male; D009200:Myocardial Contraction / Q000235:genetics; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics; D020127:Recovery of Function / Q000235:genetics; D013552:Swine; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism; D000099152:Cadherin 5
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D015703:Antigens, CD; D015820:Cadherins; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D000099152:Cadherin 5