Effects of gene delivery on collateral development in chronic hypoperfusion: Diverse effects of Angiopoietin-1 versus vascular endothelial growth factor

• Published in: Journal of the American College of Cardiology Vol. 44; no. 4; pp. 897 - 903
• Main Authors: YI FU ZHOU, STABILE, Eugenio, WALKER, Jill, SHOU, Matie, BAFFOUR, Richard, ZUXI YU, ROTT, David, YANCOPOULOS, George D, RUDGE, John S, EPSTEIN, Stephen E
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Science 18.08.2004; Elsevier Limited
• Subjects: Adenoviridae - genetics; Adenoviruses; Angiogenesis; Angiogenesis Inducing Agents - pharmacology; Angiopoietin-1 - pharmacology; Animals; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiovascular disease; Ear, External - blood supply; Endothelium, Vascular - drug effects; Gene Expression; Genetic Therapy; Ischemia; Ischemia - drug therapy; Ischemia - physiopathology; Laboratory animals; Male; Medical sciences; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - genetics; Permeability; Rabbits; Random Allocation; Regional Blood Flow; Rodents; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - pharmacology; Development; Chronic; Vascular endothelium growth factor; Comparative study; Genetic transfer
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2004.05.046

The aim of this research was to test the effects of vascular endothelial growth factor (VEGF)/angiopoietin-1 (Ang-1) on adult hypoperfused tissues. Angiopoietin-1 and VEGF act separately and synergistically in vascular development during embryogenesis. However, little is known regarding their relative roles in collateral development after chronic arterial obstruction and tissue ischemia in the adult. Central and caudal ear arteries of 32 rabbits were ligated to induce ischemia. At two months, when flow was about 65% of pre-ligation values, we injected intradermally 10(9) plaque-forming unit adenovirus with the following transgenes: Ang-1, VEGF, or a combination of both. Ear perfusion was followed up for four weeks, and vessel leakage was assessed by Evens Blue test. Before injection, flow was 65% of baseline, and endogenous VEGF levels in ischemic tissue were increased. Adenovirus-encoding VEGF gene (Ad.VEGF) at one week caused a visible inflammatory response associated with a 24% flow increase (p = 0.018). Adenovirus-encoding Ang-1 gene (Ad.Ang-1) increased flow 22% (p = 0.004) with no visible inflammation; Ad.VEGF caused three times as much vessel leakage as Ad.Ang-1 (142.5 +/- 38 vs. 49.5 +/- 9.8 ng Evens Blue/mg tissue; p < 0.001). However, at four weeks, compared with baseline, VEGF decreased flow 18% (p = 0.004), whereas Ang-1 increased tissue perfusion 26% (p < 0.001). This effect was abolished when Ad.Ang-1 was injected with soluble VEGF receptor [Ad.Flt(1-3)-Fc], which blocks VEGF-dependent signaling. Exogenous Ang-1 did not increase perfusion in a normally perfused ear, in which endogenous VEGF is not expressed. Exogenous Ang-1 enhances perfusion in hypoperfused tissues only in the presence of increased levels of endogenous VEGF. Overexpression of VEGF, however, after causing an inflammatory response, does not improve collateral blood flow.