1. Inhibition of VEGFR-2 reverses type 1 diabetes in NOD mice by abrogating insulitis and restoring islet function
- Author
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Villalta, S. Armando, Lang, Jiena, Kubeck, Samantha, Kabre, Beniwende, Szot, Gregory L., Calderon, Boris, Wasserfall, Clive, Atkinson, Mark A., Brekken, Rolf A., Pullen, Nick, Arch, Robert H., and Bluestone, Jeffrey A.
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T cells -- Physiological aspects ,Type 1 diabetes -- Genetic aspects -- Environmental aspects ,Vascular endothelial growth factor -- Physiological aspects ,Health - Abstract
The dysregulation of receptor tyrosine kinases (RTKs) in multiple cell types during chronic inflammation is indicative of their pathogenic role in autoimmune diseases. Among the many RTKs, vascular endothelial growth factor receptor (VEGFR) stands out for its multiple effects on immunity, vascularization, and cell migration. Herein, we examined whether VEGFR participated in the pathogenesis of type 1 diabetes (T1D) in nonobese diabetic (NOD) mice. We found that RTK inhibitors (RTKIs) and VEGF or VEGFR-2 antibodies reversed diabetes when administered at the onset of hyperglycemia. Increased VEGF expression promoted islet vascular remodeling in NOD mice, and inhibition of VEGFR activity with RTKIs abrogated the increase in islet vascularity, impairing T-cell migration into the islet and improving glucose control. Metabolic studies confirmed that RTKIs worked by preserving islet function, as treated mice had improved glucose tolerance without affecting insulin sensitivity. Finally, examination of human pancreata from patients with T1D revealed that VEGFR-2 was confined to the islet vascularity, which was increased in inflamed islets. Collectively, this work reveals a previously unappreciated role for VEGFR-2 signaling in the pathogenesis of T1D by controlling T-cell accessibility to the pancreatic islets and highlights a novel application of VEGFR-2 antagonists for the therapeutic treatment of T1D., In type 1 diabetes (T1D), genetic and environmental risk factors lead to immune dysregulation, provoking an autoimmune response directed toward insulin-producing β-cells of the islets of Langerhans. Previous investigations have [...]
- Published
- 2013
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