title: Overexpressing IRS1 in Endothelial Cells Enhances Angioblast Differentiation and Wound Healing in Diabetes and Insulin Resistance.
abstract: The effect of enhancing insulin's actions in endothelial cells (ECs) to improve angiogenesis and wound healing was studied in obesity and diabetes. Insulin receptor substrate 1 (IRS1) was overexpressed in ECs using the VE-cadherin promoter to create ECIRS1 TG mice, which elevated pAkt activation and expressions of vascular endothelial growth factor (VEGF), Flk1, and VE-cadherin in ECs and granulation tissues (GTs) of full-thickness wounds. Open wound and epithelialization rates and angiogenesis significantly improved in normal mice and high fat (HF) diet-induced diabetic mice with hyperinsulinemia in ECIRS1 TG versus wild type (WT), but not in insulin-deficient diabetic mice. Increased angioblasts and EC numbers in GT of ECIRS1 mice were due to proliferation in situ rather than uptake. GT in HF-fed diabetic mice exhibited parallel decreases in insulin and VEGF-induced pAkt and EC numbers by >50% without changes in angioblasts versus WT mice, which were improved in ECIRS1 TG mice on normal chow or HF diet. Thus, HF-induced diabetes impaired angiogenesis by inhibiting insulin signaling in GT to decrease the differentiation of angioblasts to EC, which was normalized by enhancing insulin's action targeted to EC, a potential target to improve wound healing in diabetes and obesity.
authors.affiliation: Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Katagiri
authors.affiliation: Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors.forename: Kyoungmin
authors.initials: K
authors.lastname: Park
authors.affiliation: Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Joslin Diabetes Center, Havard Medical School, Boston, MA.
authors.forename: Tata Nageswara
authors.initials: TN
authors.lastname: Rao
authors.affiliation: Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors.forename: Mogher
authors.initials: M
authors.lastname: Khamaisi
authors.affiliation: Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yokomizo
authors.affiliation: Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
authors.forename: Akira
authors.initials: A
authors.lastname: Mima
authors.affiliation: Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Luca
authors.initials: L
authors.lastname: Lancerotto
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Joslin Diabetes Center, Havard Medical School, Boston, MA.
authors.forename: Amy
authors.initials: A
authors.lastname: Wagers
authors.affiliation: Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Orgill
authors.affiliation: Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA george.king@joslin.harvard.edu.
authors.forename: George L
authors.initials: GL
authors.lastname: King
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D055504:Insulin Receptor Substrate Proteins; D042461:Vascular Endothelial Growth Factor A