Insulin-like growth factor I plasmid therapy promotes in vivo angiogenesis.
Angiogenesis, the formation of neovessels from the endothelium of preexisting vessels, is stimulated by soluble angiogenic factors. Insulin-like growth factor I (IGF-I) stimulates myogenesis and induces nerve regeneration after injury, and it has been shown to stimulate angiogenesis. However, the in vivo angiogenic effects of IGF-I in regenerating and diabetic muscle have yet to be described. Therefore, we studied the effects of human IGF-I (hIGF-I) delivered by a plasmid-mediated therapy on angiogenesis in mouse models of these two conditions. Plasmid hIGF-I was delivered to the injured tibialis muscle by direct intramuscular injection followed by electroporation. Initial experiments compared two muscle-specific hIGF-I-expressing constructs containing either a skeletal actin 3'UTR (pAV2001) or a human growth hormone (GH) 3'UTR (pAV2002). Skeletal actin 3'UTR mediates sequestration of hIGF-I in the muscle and was more active, while the GH 3'UTR mediated release of IGF-I into the circulation. Treatment of regenerating muscle with pAV2001 and sequestration of IGF-I in muscle led to increased expression of vascular endothelial growth factor (VEGF) and VEGF receptors fetal liver kinase-1 and FmS-like tyrosine kinase receptor-1, as well as platelet endothelial cell adhesion molecule-1, on endothelial cells. These results indicate that IGF-I can amplify angiogenic responses in regenerating muscle. In a mouse diabetic model, plasmid-mediated IGF-I therapy reversed diabetic microangiopathy, as shown by increased angiogenesis and arterial flow as analyzed by Doppler imaging. These studies show that plasmid IGF-I delivery and sequestration in muscle can augment angiogenesis in regenerating muscle and increase blood flow and angiogenesis in the diabetic limb.
Rabinovsky
Eric D
ED
Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. ericr@bcm.tmc.edu
Draghia-Akli
Ruxandra
R
D020413:3' Untranslated Regions / Q000235:genetics; D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D003925:Diabetic Angiopathies / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D013006:Growth Hormone / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D007511:Ischemia / Q000209:etiology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008813:Mice, Inbred ICR; D018482:Muscle, Skeletal / Q000098:blood supply / Q000473:pathology; D018919:Neovascularization, Physiologic; D010957:Plasmids / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D020413:3' Untranslated Regions; D000199:Actins; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D040262:Receptors, Vascular Endothelial Growth Factor