Overexpressing IRS1 in endothelial cells enhances angioblast differentiation and wound healing in diabetes and insulin resistance

Sayaka Katagiri, Kyoungmin Park, Yasutaka Maeda, Tata Nageswara Rao, Mogher Khamaisi, Qian Li, Hisashi Yokomizo, Akira Mima, Luca Lancerotto, Amy Wagers, Dennis P. Orgill, George L. King

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 insulindeficient 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.

Original languageEnglish
Pages (from-to)2760-2771
Number of pages12
JournalDiabetes
Volume65
Issue number9
DOIs
Publication statusPublished - Sep 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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  • Cite this

    Katagiri, S., Park, K., Maeda, Y., Rao, T. N., Khamaisi, M., Li, Q., Yokomizo, H., Mima, A., Lancerotto, L., Wagers, A., Orgill, D. P., & King, G. L. (2016). Overexpressing IRS1 in endothelial cells enhances angioblast differentiation and wound healing in diabetes and insulin resistance. Diabetes, 65(9), 2760-2771. https://doi.org/10.2337/db15-1721