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, Roll A., Pullen, Nick, Arch, Robert H., and Bluestone, Jeffrey A.
- Subjects
VASCULAR endothelial growth factor receptors ,DIABETES ,PATHOLOGICAL physiology ,LABORATORY mice ,PROTEIN-tyrosine kinase inhibitors ,IMMUNOGLOBULINS ,T cells ,CELLULAR signal transduction ,MAMMALS - 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 the pathogenesis of type 1 diabetes (TID) in nonobese diabetic (NOD) mice. We found that RTK inhibitors (RTKIs) and VEGF 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 VEGF 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 TID revealed that VEGFR-2 was confined to the islet vascularity, which was increased in inflamed islets. Collectively, this work reveal a previously unappreciated role for VEGFR-2 signaling in the pathogenesis of TID by controlling T-cell accessibility to the pancreatic islets and highlights a novel application of VEGFR-2 antagonists for the therapeutic treatment of T1D. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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