Overexpressing IRS1 in Endothelial Cells Enhances Angioblast Differentiation and Wound Healing in Diabetes and Insulin Resistance

• Published in: Diabetes (New York, N.Y.) Vol. 65; no. 9; pp. 2760 - 2771
• Main Authors: Katagiri, Sayaka, Park, Kyoungmin, Maeda, Yasutaka, Rao, Tata Nageswara, Khamaisi, Mogher, Li, Qian, Yokomizo, Hisashi, Mima, Akira, Lancerotto, Luca, Wagers, Amy, Orgill, Dennis P, King, George L
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.09.2016
• Subjects: Angiogenesis; Animals; Cells; Complications; Diabetes; Diabetes Mellitus, Experimental - metabolism; Diet, High-Fat - adverse effects; Endothelial Cells - metabolism; Flow Cytometry; Fluorescent Antibody Technique; Immunoblotting; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance - genetics; Insulin Resistance - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Real-Time Polymerase Chain Reaction; Rodents; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Wound Healing - genetics; Wound Healing - physiology
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db15-1721

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.