Cell and molecular mechanisms of insulin-induced angiogenesis.
Angiogenesis, the development of new blood vessel from pre-existing vessels, is a key process in the formation of the granulation tissue during wound healing. The appropriate development of new blood vessels, along with their subsequent maturation and differentiation, establishes the foundation for functional wound neovasculature. We performed studies in vivo and used a variety of cellular and molecular approaches in vitro to show that insulin stimulates angiogenesis and to elucidate the signalling mechanisms by which this protein stimulates microvessel development. Mice skin injected with insulin shows longer vessels with more branches, along with increased numbers of associated alpha-smooth muscle actin-expressing cells, suggesting the appropriate differentiation and maturation of the new vessels. We also found that insulin stimulates human microvascular endothelial cell migration and tube formation, and that these effects occur independently of VEGF/VEGFR signalling, but are dependent upon the insulin receptor itself. Downstream signalling pathways involve PI3K, Akt, sterol regulatory element-binding protein 1 (SREBP-1) and Rac1; inhibition of these pathways results in elimination of endothelial cell migration and tube formation and significantly decreases the development of microvessels. Our findings strongly suggest that insulin is a good candidate for the treatment of ischaemic wounds and other conditions in which blood vessel development is impaired.
Liu
Yan
Y
Department of Burn, Ruijin Hospital, JiaoTong University Medical College, Shanghai, China.
Petreaca
Melissa
M
Martins-Green
Manuela
M
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000166:cytology / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000098:blood supply / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013997:Time Factors; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D007328:Insulin; D051780:Sterol Regulatory Element Binding Protein 1; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein