Journal Article

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

Jin Chen, Maureen Gannon, Peter O. Wiebe, Jeannelle Kantz, Alvin C. Powers, Masakazu Shiota, Alena Shostak, Chad Carr, Zhongyi Chen, W. Gray Jerome, Wendell Nicholson, Thomas Jetton, Greg Poffenberger, Marcela Brissova, H. Scott Baldwin, David M. Bader

2006

Overview

Pancreatic Islet Production of Vascular Endothelial Growth Factor-A Is Essential for Islet Vascularization, Revascularization, and Function Marcela Brissova 1 , Alena Shostak 1 , Masakazu Shiota 2 , Peter O. Wiebe 2 , Greg Poffenberger 1 , Jeannelle Kantz 2 , Zhongyi Chen 1 , Chad Carr 1 , W. Gray Jerome 3 4 , Jin Chen 4 5 , H. Scott Baldwin 6 , Wendell Nicholson 1 , David M. Bader 7 , Thomas Jetton 8 , Maureen Gannon 1 2 and Alvin C. Powers 1 2 9 1 Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 2 Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 3 Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 4 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 5 Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 6 Division of Pediatric Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 7 Stahlman Laboratory, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 8 Division of Endocrinology and Metabolism, Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont 9 Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 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. Ang, angiopoietin VEGF, vascular endothelial growth factor 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. DIABETES

• Publisher: American Diabetes Association
• Subject: Angiogenesis / Animals / Biological and medical sciences / Blood Flow Velocity / Blood glucose / Blood sugar / Blood vessels / Diabetes / Diabetes. Impaired glucose tolerance / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Health aspects / Insulin / Insulin - blood / Insulin - metabolism / Insulin Secretion / Islets of Langerhans - blood supply / Islets of Langerhans - metabolism / Islets of Langerhans - ultrastructure / Kinases / Laboratories / Lectins / Medical sciences / Mice / Mice, Knockout / Microscopy, Electron / Morphogenesis / Neovascularization, Physiologic / Pancreas / Pancreas - blood supply / Pancreas - growth & development / Pancreas - physiology / Pancreatic beta cells / Transplants & implants / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - deficiency / Vascular Endothelial Growth Factor A - genetics / Vascular Endothelial Growth Factor A - physiology