Synergistic effect of angiopoietin-1 and vascular endothelial growth factor on neoangiogenesis in hypercholesterolemic rabbit model with acute hindlimb ischemia.
Vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) are essential for vascular integrity and development. The purpose of the study was to test the hypothesis that Ang1 will promote angiogenic response to VEGF in the spontaneous Watanabe heritable hypercholesterolemic (WHHL) rabbit model of acute hindlimb ischemia. Immediately after the ligation of the external iliac artery and the excision of the common and superficial femoral artery in one female WHHL rabbit, 250 microg of phVEGF(165) (n = 8), 500 microg of pAng1* (n = 8), or 250 microg of phVEGF(165) plus 500 microg of pAng1* (n = 8) was injected intramuscularly into the ischemic hindlimb muscles. Gross appearance of ischemic limb, collateral vessel formation and limb perfusion were assessed 30 days after treatment. The incidence of ischemic limb necrosis was higher in the animals treated by phVEGF(165) or by pAng1* than in those treated by phVEGF(165) plus pAng1* (100%, 75% and 14.3%, respectively; P = 0.002). Animals in the combination therapy group had a significantly higher calf blood pressure ratio at day 30 (VEGF plus Ang1* = 0.84 +/- 0.06; VEGF = 0.54 +/- 0.01; Ang1* = 0.59 +/- 0.05; P < 0.01). A combination therapy of VEGF plus Ang*1 had a significantly higher (P < 0.01) angiographic score than either therapy alone. Capillary density (P < 0.05) and capillary/muscle fiber ratio (P < 0.01) of the combination therapy group were also significantly higher than that of either therapy alone. In conclusion, Ang1 can potentiate the angiogenic response to VEGF in the hyperlipidemic rabbit model of acute hindlimb ischemia. Intramuscular administration of cytokines on revascularization of the ischemic hindlimb model of hyperlipidemic rabbit is feasible.
Shyu
Kou-Gi
KG
Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen-Chang Road, Taipei 111, Taiwan. suyukg@ms12.hinet.net
Chang
Hang
H
Isner
Jeffrey M
JM
D043925:Angiogenesis Inducing Agents / Q000235:genetics / Q000494:pharmacology*; D000792:Angiography; D042683:Angiopoietin-1; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000235:genetics / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006614:Hindlimb / Q000098:blood supply* / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D007273:Injections, Intramuscular; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology*; D007511:Ischemia / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D008222:Lymphokines / Q000235:genetics / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000098:blood supply / Q000503:physiopathology; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D011817:Rabbits; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D008562:Membrane Glycoproteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors