Pancreatic Islet Production of Vascular Endothelial Growth Factor-A Is Essential for Islet Vascularization, Revascularization, and Function

  1. Marcela Brissova1,
  2. Alena Shostak1,
  3. Masakazu Shiota2,
  4. Peter O. Wiebe2,
  5. Greg Poffenberger1,
  6. Jeannelle Kantz2,
  7. Zhongyi Chen1,
  8. Chad Carr1,
  9. W. Gray Jerome34,
  10. Jin Chen45,
  11. H. Scott Baldwin6,
  12. Wendell Nicholson1,
  13. David M. Bader7,
  14. Thomas Jetton8,
  15. Maureen Gannon12 and
  16. Alvin C. Powers129
  1. 1Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  2. 2Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee
  3. 3Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee
  4. 4Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee
  5. 5Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee
  6. 6Division of Pediatric Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  7. 7Stahlman Laboratory, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  8. 8Division of Endocrinology and Metabolism, Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont
  9. 9Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee
  1. Address correspondence and reprint requests to Alvin C. Powers, Division of Diabetes, Endocrinology, and Metabolism, 715 PRB, Vanderbilt University, Nashville, TN 37232. E-mail: al.powers{at}vanderbilt.edu

Abstract

To investigate molecular mechanisms controlling islet vascularization and revascularization after transplantation, we examined pancreatic expression of three families of angiogenic factors and their receptors in differentiating endocrine cells and adult islets. Using intravital lectin labeling, we demonstrated that development of islet microvasculature and establishment of islet blood flow occur concomitantly with islet morphogenesis. Our genetic data indicate that vascular endothelial growth factor (VEGF)-A is a major regulator of islet vascularization and revascularization of transplanted islets. In spite of normal pancreatic insulin content and β-cell mass, mice with β-cell–reduced VEGF-A expression had impaired glucose-stimulated insulin secretion. By vascular or diffusion delivery of β-cell secretagogues to islets, we showed that reduced insulin output is not a result of β-cell dysfunction but rather caused by vascular alterations in islets. Taken together, our data indicate that the microvasculature plays an integral role in islet function. Factors modulating VEGF-A expression may influence islet vascularity and, consequently, the amount of insulin delivered into the systemic circulation.

Footnotes

  • Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted July 19, 2006.
    • Received May 18, 2006.
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