Upregulation of non-β Cell-derived Vascular Endothelial Growth Factor A Increases Small Clusters of Insulin-producing Cells in the Pancreas

Abstract

Background:

Pancreatic β cell-derived vascular endothelial growth factor A (VEGF-A) contributes to normal β cell function. We therefore hypothesized that non-β cell-derived VEGF-A may affect its properties in adult mice.

Methods:

We generated transgenic mice expressing human VEGF-A (hVEGF-A) in a visceral smooth muscle cell (SMC)-dominant manner under the control of the transgelin (Tagln/SM22α) promoter via a tamoxifen-induced Cre/loxP recombination system (SM-CreER^T2/hVEGF mice).

SM-CreER^T2/hVEGF mice received tamoxifen orally followed by microscopic examination of their pancreas 4 weeks after the hVEGF-A induction. The number of clusters of insulin-producing cells (IPCs) in islets, pancreatic ducts, and individual IPCs were counted.

Results:

The number of small IPC clusters (100–215 μm²) in the pancreas increased significantly in SM-CreER^T2/hVEGF mice compared with SM-CreER^T2(Ki) mice (473 out of 1 992 counts vs. 199 out of 976 counts, p<0.05), although total IPC area and the number of pancreatic duct IPCs, in proportion to exocrine area, were similar between the 2 groups. Although most small IPC clusters observed in SM-CreER^T2/hVEGF mice were not accompanied by α and/or δ cells, some were attached to a single or a few α cells. An STZ-induced diabetic state in SM-CreER^T2/hVEGF mice was slightly ameliorated, with only one point of significance 12 weeks after STZ administration, compared with SM-CreER^T2(Ki) mice.

Conclusion:

Upregulation of non-β cell-derived VEGF-A may alter the composition of pancreatic IPCs by increasing the number of small IPC clusters. These findings provide new information on the role of non-β cell-derived VEGF-A to IPC regeneration and insulin production.

Key words

diabetes - islet - smooth muscle cell - streptozotocin

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