title: Vascular endothelial insulin/IGF-1 signaling controls skin wound vascularization.
abstract: Type 2 diabetes mellitus affects 6% of western populations and represents a major risk factor for the development of skin complications, of which impaired wound healing, manifested in e.g. "diabetic foot ulcer", is most prominent. Impaired angiogenesis is considered a major contributing factor to these non-healing wounds. At present it is still unclear whether diabetes-associated wound healing and skin vascular dysfunction are direct consequences of impaired insulin/IGF-1 signaling, or secondary due to e.g. hyperglycemia. To directly test the role of vascular endothelial insulin signaling in the development of diabetes-associated skin complications and vascular function, we inactivated the insulin receptor and its highly related receptor, the IGF-1 receptor, specifically in the endothelial compartment of postnatal mice, using the inducible Tie-2CreERT (DKO(IVE)) deleter. Impaired endothelial insulin/IGF-1 signaling did not have a significant impact on endothelial homeostasis in the skin, as judged by number of vessels, vessel basement membrane staining intensity and barrier function. In contrast, challenging the skin through wounding strongly reduced neo-angiogenesis in DKO(IVE) mice, accompanied by reduced granulation tissue formation reduced. These results show that endothelial insulin/IGF signaling is essential for neo-angiogenesis upon wounding, and imply that reduced endothelial insulin/IGF signaling directly contributes to diabetes-associated impaired healing.
authors.affiliation: Department of Dermatology, University of Cologne, Germany.
authors.forename: Saeed Yadranji
authors.initials: SY
authors.lastname: Aghdam
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Eming
authors.forename: Sebastian
authors.initials: S
authors.lastname: Willenborg
authors.forename: Brit
authors.initials: B
authors.lastname: Neuhaus
authors.forename: Carien M
authors.initials: CM
authors.lastname: Niessen
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.forename: Jens C
authors.initials: JC
authors.lastname: Bruning
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D006097:Granulation Tissue / Q000473:pathology / Q000503:physiopathology; D006706:Homeostasis; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D012867:Skin / Q000098:blood supply* / Q000473:pathology; D014945:Wound Healing
chemical_list: D007328:Insulin; D007334:Insulin-Like Growth Factor I