Structural stability of neoangiogenic intramyocardial microvessels supports functional recovery in chronic ischemic myocardium

J Mol Cell Cardiol. 2008 Jul;45(1):70-80. doi: 10.1016/j.yjmcc.2008.04.007. Epub 2008 Apr 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae*
  • Angiopoietin-1 / biosynthesis*
  • Angiopoietin-1 / genetics
  • Angiopoietin-2 / biosynthesis*
  • Angiopoietin-2 / genetics
  • Animals
  • Antigens, CD / metabolism
  • Arterioles / metabolism
  • Arterioles / pathology
  • Cadherins / metabolism
  • Chronic Disease
  • Coronary Circulation / genetics
  • Coronary Vessels / metabolism
  • Coronary Vessels / pathology
  • Disease Models, Animal
  • Echocardiography, Doppler
  • Endothelium / metabolism
  • Female
  • Genetic Therapy / methods
  • Male
  • Myocardial Contraction / genetics
  • Myocardial Ischemia / diagnostic imaging
  • Myocardial Ischemia / metabolism*
  • Myocardial Ischemia / pathology
  • Myocardial Ischemia / therapy
  • Myocardium / metabolism
  • Myocardium / pathology
  • Neovascularization, Physiologic* / genetics
  • Recovery of Function* / genetics
  • Swine
  • Time Factors
  • Vascular Endothelial Growth Factor A / biosynthesis*
  • Vascular Endothelial Growth Factor A / genetics
  • beta Catenin / metabolism


  • Angiopoietin-1
  • Angiopoietin-2
  • Antigens, CD
  • Cadherins
  • Vascular Endothelial Growth Factor A
  • beta Catenin
  • cadherin 5