Vascular Endothelial Growth Factor A Coordinates Pancreatic Islet Vascularization, Innervation, and Function

Abstract

Pancreatic islets are miniature endocrine organs that regulate glucose homeostasis. Islets are highly vascularized and richly innervated, but the molecular mechanisms directing this organization are incompletely defined. Vascular endothelial growth factor A (VEGF-A) is crucial for the recruitment of endothelial cells during islet development and vascularization. Once thought to be an endothelial cell-specific signaling molecule, VEGF-A can also signal directly to neurons and glia. This Dissertation defined a new role for VEGF-A in regulating islet innervation during development and expanded our understanding of VEGF-A in the maintenance of mature islet vascularization and function. First, the VEGF-Á-mediated patterning of the intraislet vasculature was found to be required for the development of islet innervation. In mature islets, nerves are closely associated with capillaries, but islet vascularization developmentally precedes islet innervation. Genetic mouse models showed that VEGF-A is a critical mediator of both processes, although VEGF-A is not a direct signal to islet nerves. Instead, islet-derived VEGF-A is required for the formation of the intraislet vasculature during embryogenesis, and postnatally, nerve fibers travel along these capillaries in a VEGF-A-independent manner to innervate islet cells. These results demonstrated that islet vascularization and innervation are developmentally interconnected, and that islet-derived VEGF-A is a principal coordinator of islet formation. Furthermore, the role of VEGF-A in maintaining the vascularization and function of mature islets was defined using a mouse model of tamoxifen-inducible gene inactivation. In development of this model, an islet transplantation bioassay was designed to demonstrate that tamoxifen-inducible Cre-loxP recombination in adult mice in vivo occurs significantly longer than suggested by prior studies, which has broad implications for the use of tamoxifen-inducible mouse models in biomedical research. In these studies, inactivation of VEGF-A in â-cells of adult mice reduced islet vascularity and impaired glucose tolerance, but surprisingly had little impact on â-cell mass maintenance, gene expression, or insulin secretion in vitro. These experiments showed that mature pancreatic â-cells can tolerate a significant and prolonged reduction in intraislet capillary density and still maintain relatively normal function.