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- Title
Overexpressing IRS1 in Endothelial Cells Enhances Angioblast Differentiation and Wound Healing in Diabetes and Insulin Resistance.
- Authors
Katagiri, Sayaka; Park, Kyoungmin; Maeda, Yasutaka; Nageswara Rao, Tata; Khamaisi, Mogher; Qian Li; Hisashi Yokomizo; Mima, Akira; Lancerotto, Luca; Wagers, Amy; Orgill, Dennis P.; King, George L.; Rao, Tata Nageswara; Li, Qian; Yokomizo, Hisashi
- 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.
- Subjects
INSULIN; ENDOTHELIAL cells; NEOVASCULARIZATION; WOUND healing; OBESITY; DIABETES; ANIMAL experimentation; CARRIER proteins; DIET; EPITHELIAL cells; FLOW cytometry; FLUORESCENT antibody technique; IMMUNOBLOTTING; INSULIN resistance; MICE; POLYMERASE chain reaction; RESEARCH funding; VASCULAR endothelial growth factors
- Publication
Diabetes, 2016, Vol 65, Issue 9, p2760
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db15-1721