VEGF expression in pancreatic islets is important for insulin delivery into the vascular system.
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Pancreatic islets have greater vascularity and blood flow than surrounding pancreatic exocrine tissue; the responsible molecular mechanisms are incompletely defined. By immunocytochemistry, we found that VEGF was expressed in all four islet cell types at a much greater level than in surrounding acinar cells. To test the hypothesis that VEGF expression is important for islet vascularization and function, we inactivated VEGF-A in a þ cell-specific manner by breeding RIP-Cre and VEGF-A-loxP mice. While adult mice -/- for VEGF-A þ cells had normal pancreatic weight, insulin content, and islet architecture, -/- mice cleared glucose ollowing intraperitoneal glucose at a considerably slower rate than +/+ mice. Plasma insulin levels, normalized for blood glucose after glucose administration, were significantly lower in -/- mice (117 ± 12 ng/g; n = 12) compared to +/+ mice (229 ± 17 ng/g; n = 12). Vascular density within islets was significantly reduced in -/- mice (760 ± 38 vessels/mm2; n = 3) compared to wild type mice (1581 ± 95 vessels/mm 2; n = 3). Vascularization parameters such as area/vessel (83 ± 6 µ 2 in islets of -/- mice) and perimeter/vessel (46 ± 2 µ in islets of -/- mice) were also diminished in comparison to +/+ mice (120 ± 21 µ 2; 55 ± 4 µ), indicating a reduction in the number of capillaries per islet, vessel size, and/or branching. Isolated islets from -/- mice and +/+ mice had a similar insulin secretory pattern in a perifusion system indicating similar islet cell function. By electron microscopy, intra-islet endothelial cells in the pancreas from -/- mice had disordered endothelial cell ultrastructure and reduced fenestration. Reduced islet expression of VEGF resulted in reduced islet vascularization, disordered endothelial cell structure, and a pre-diabetic phenotype similar to some defects in þ cell gene expression. These data suggest that normal islet vascularization and insulin delivery into the vascular system requires islet expression of VEGF-A. These observations also have implications for the revascularization of transplanted islets.
The Medical Student Summer Research Training Program is supported by the Vanderbilt Short Term Research Training Program for Medical Students (NIH grant DK007383) and the Vanderbilt Diabetes Research and Training Center (NIH grant DK20593).