Elevated Vascular Endothelial Growth Factor Production in Islets Improves Islet Graft Vascularization

  1. Nan Zhang1,
  2. Anja Richter1,
  3. Jenny Suriawinata1,
  4. Sonal Harbaran1,
  5. Jennifer Altomonte1,
  6. Lin Cong1,
  7. Haojiang Zhang1,
  8. Keying Song2,
  9. Marcia Meseck1,
  10. Jonathan Bromberg1 and
  11. Hengjiang Dong12
  1. 1Carl Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York
  2. 2Division of Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, New York
  1. Address correspondence and reprint requests to Hengjiang Dong, Ph.D., Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1496, New York, NY 10029. E-mail: hengjiang.dong{at}mssm.edu

Abstract

Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, of which only ∼30% become stably engrafted. Rapid and adequate revascularization of transplanted islets is important for islet survival and function. Delayed and insufficient revascularization can deprive islets of oxygen and nutrients, resulting in islet cell death and early graft failure. To improve islet revascularization, we delivered human vascular endothelial growth factor (VEGF) cDNA to murine islets, followed by transplantation under the renal capsule in diabetic mice. Diabetic animals receiving a marginal mass of 300 islets that were pretransduced with a VEGF vector exhibited near normoglycemia. In contrast, diabetic mice receiving an equivalent number of islets that were transduced with a control vector remained hyperglycemic. Immunohistochemistry with anti-insulin and anti-CD31 antibodies revealed a relatively higher insulin content and greater degree of microvasculature in the VEGF vector–transduced islet grafts, which correlated with significantly improved blood glucose profiles and enhanced insulin secretion in response to glucose challenge in this group of diabetic recipient mice. These results demonstrate that VEGF production in islets stimulates graft angiogenesis and enhances islet revascularization. This mechanism might be explored as a novel strategy to accelerate islet revascularization and improve long-term survival of functional islet mass posttransplantation.

Footnotes

    • Accepted January 7, 2004.
    • Received July 9, 2003.
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