Angiopoietin-1 promotes functional neovascularization that relieves ischemia by improving regional reperfusion in a swine chronic myocardial ischemia model

Abstract

SummaryThis 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 lm) 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.

Coadministration of Endothelial and Smooth Muscle Progenitor Cells Enhances the Efficiency of Proangiogenic Cell-Based Therapy

“…In this view, Ang-1 has been reported to significantly increase arteriolar density in ischemic areas. 22,32 Similarly, we showed that combined administration of EPCs and SMPCs upregulated 24 suggesting that SMPC-released Ang-1 may also control endothelial cell network formation. Finally, Ang-1 may act on Tie2-expressing EPCs.…”

“…20 In addition, direct administration of plasmid encoding for Ang-1 increases postischemic revascularization after hindlimb ischemia and myocardial infarction. 21,22 Moreover, the receptor tyrosine kinase Tie2 is expressed on endothelial cells and hematopoietic stem cells. 23 Ang-1 interaction with its receptor Tie2 induces intracellular signaling promoting endothelial cells survival, migration, sprouting, and network formation.…”

Angiopoietin-2 Impairs Revascularization After Limb Ischemia

“…36 Activities of angiopoietins appear to be context dependent, and doses have to be carefully balanced to accomplish pro-and antiangiogenic activities. Ang-1 has been shown to promote functional neovascularization and improvement of reperfusion after myocardial ischemia in the swine 37 and, together with VEGF, decrease the (B) were quantitatively assessed to identify the influence of Ang-2 on endothelial/SMC interaction. As shown in A, collateral artery wall thickness was significantly reduced in Ang-2 DT animals.…”

Cardiac gene therapy in large animals: bridge from bench to bedside

“…VEGF 165 has been the most frequently tested growth factor in large animal gene transfer studies. 14,[42][43][44][45][46][47][48][49][50][51][52][53][54] This form enhances collateral formation and myocardial perfusion in ameroid constrictor chronic ischemia models 46,48,50,54 as well as in coronary artery ligation ischemia models. 14,51,52 VEGF 121 gene transfer was evaluated in the chronic ischemia model, 20,55 and the pacing induced heart failure model, 26 showing improved myocardial perfusion and preserved cardiac function.…”

“…Other genes delivered to promote angiogenesis in large animals include CD151, 66 inducible nitric oxide synthase, 18 Angiopoietin-1 (ref. 53) and hypoxia inducible factor-1a. 67 Gene transfer of Angiopoietin-1, hypoxia inducible factor-1a and CD151 successfully increased myocardial perfusion of the ischemic area.…”