Inhibition of VEGFR-2 reverses type 1 diabetes in nod mice by abrogating insulitis and restoring islet function

S. Armando Villalta, Jiena Lang, Samantha Kubeck, Beniwende Kabre, Gregory L. Szot, Boris Calderon, Clive Wasserfall, Mark A. Atkinson, Rolf A. Brekken, Nick Pullen, Robert H. Arch, Jeffrey A. Bluestone

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2870-2878
Number of pages9
JournalDiabetes
Volume62
Issue number8
DOIs
StatePublished - Aug 1 2013

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Villalta, S. A., Lang, J., Kubeck, S., Kabre, B., Szot, G. L., Calderon, B., Wasserfall, C., Atkinson, M. A., Brekken, R. A., Pullen, N., Arch, R. H., & Bluestone, J. A. (2013). Inhibition of VEGFR-2 reverses type 1 diabetes in nod mice by abrogating insulitis and restoring islet function. Diabetes, 62(8), 2870-2878. https://doi.org/10.2337/db12-1619