Exp Clin Endocrinol Diabetes 2014; 122(05): 308-315
DOI: 10.1055/s-0034-1371811
Article
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

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

K. Takenouchi
1   Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
,
B. Shrestha
1   Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
,
M. Yamakuchi
1   Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
,
N. Yoshinaga
2   Department of Ophthalmology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
,
N. Arimura
2   Department of Ophthalmology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
,
H. Kawaguchi
3   Department of Veterinary Experimental Animal Science, Faculty of Agriculture, Kagoshima University, Korimoto, Kagoshima, Japan
,
T. Nagasato
4   Systems Biology in Thromboregulation, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
,
R. Feil
5   Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany
,
K. Kawahara
6   Laboratory of Functional Foods, Department of Biomedical Engineering Osaka Institute of Technology, Osaka, Japan
,
T. Sakamoto
2   Department of Ophthalmology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
,
I. Maruyama
4   Systems Biology in Thromboregulation, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
,
T. Hashiguchi
1   Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan
› Author Affiliations
Further Information

Publication History

received 06 February 2014
first decision 06 February 2014

accepted 26 February 2014

Publication Date:
16 May 2014 (online)

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-CreERT2/hVEGF mice).

SM-CreERT2/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-CreERT2/hVEGF mice compared with SM-CreERT2(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-CreERT2/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-CreERT2/hVEGF mice was slightly ameliorated, with only one point of significance 12 weeks after STZ administration, compared with SM-CreERT2(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.

 
  • References

  • 1 Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by signals from blood vessels. Science 2001; 294: 564-567
  • 2 Lammert E, Gu G, McLaughlin M et al. Role of VEGF-A in vascularization of pancreatic islets. Curr Biol 2003; 13: 1070-1074
  • 3 Brissova M, Shostak A, Shiota M et al. Pancreatic islet production of vascular endothelial growth factor-A is essential for islet vascularization, revascularization, and function. Diabetes 2006; 55: 2974-2985
  • 4 Kuhbandner S, Brummer S, Metzger D et al. Temporally controlled somatic mutagenesis in smooth muscle. Genesis 2000; 28: 15-22
  • 5 Feil S, Hofmann F, Feil R. SM22alpha modulates vascular smooth muscle cell phenotype during atherogenesis. Circ Res 2004; 94: 863-865
  • 6 Sato M, Yasuoka Y, Kodama H et al. New approach to cell lineage analysis in mammals using the Cre-loxP system. Mol Reprod Dev 2000; 56: 34-44
  • 7 Shrestha B, Hashiguchi T, Ito T et al. B cell-derived vascular endothelial growth factor A promotes lymphangiogenesis and high endothelial venule expansion in lymph nodes. J Immunol 2010; 184: 4819-4826
  • 8 Hem A, Smith AJ, Solberg P. Saphenous vein puncture for blood sampling of the mouse, rat, hamster, gerbil, guinea pig, ferret and mink. Lab Anim 1998; 32: 364-368
  • 9 Kiba T, Kintaka Y, Nakada E et al. High-quality RNA extraction from rat pancreas for microarray analysis. Pancreas 2007; 35: 98-100
  • 10 Niwa H, Yamamura K, Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 1991; 108: 193-199
  • 11 Bonner-Weir S, Baxter LA, Schuppin GT et al. A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes 1993; 42: 1715-1720
  • 12 Dor Y, Brown J, Martinez OI et al. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 2004; 429: 41-46
  • 13 Xu X, D’Hoker J, Stange G et al. Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 2008; 132: 197-207
  • 14 Zajicek G, Arber N, Schwartz-Arad D et al. Streaming pancreas: islet cell kinetics. Diabetes Res 1990; 13: 121-125
  • 15 Zulewski H, Abraham EJ, Gerlach MJ et al. Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 2001; 50: 521-533
  • 16 Best M, Carroll M, Hanley NA et al. Embryonic stem cells to beta-cells by understanding pancreas development. Mol Cell Endocrinol 2008; 288: 86-94
  • 17 Murtaugh LC. Pancreas and beta-cell development: from the actual to the possible. Development 2007; 134: 427-438
  • 18 Zaret KS, Grompe M. Generation and regeneration of cells of the liver and pancreas. Science 2008; 322: 1490-1494
  • 19 Lenzen S. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 2008; 51: 216-226
  • 20 Demeterco C, Hao E, Lee SH et al. Adult human beta-cell neogenesis?. Diabetes Obes Metab 2009; 11 (Suppl. 04) 46-53
  • 21 Ogihara T, Fujitani Y, Uchida T et al. Combined expression of transcription factors induces AR42J-B13 cells to differentiate into insulin-producing cells. Endocr J 2008; 55: 691-698
  • 22 Zhou Q, Brown J, Kanarek A et al. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008; 455: 627-632
  • 23 Inada A, Nienaber C, Katsuta H et al. Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci USA 2008; 105: 19915-19919
  • 24 Talchai C, Lin HV, Kitamura T et al. Genetic and biochemical pathways of beta-cell failure in type 2 diabetes. Diabetes Obes Metab 2009; 11 (Suppl. 04) 38-45
  • 25 Olsson AK, Dimberg A, Kreuger J et al. VEGF receptor signalling – in control of vascular function. Nat Rev Mol Cell Biol 2006; 7: 359-371
  • 26 Doronzo G, Viretto M, Russo I et al. Effects of high glucose on vascular endothelial growth factor synthesis and secretion in aortic vascular smooth muscle cells from obese and lean zucker rats. Int J Mol Sci 2012; 13: 9478-9488
  • 27 Oberg-Welsh C, Sandler S, Andersson A et al. Effects of vascular endothelial growth factor on pancreatic duct cell replication and the insulin production of fetal islet-like cell clusters in vitro. Mol Cell Endocrinol 1997; 126: 125-132
  • 28 Klement GL, Yip TT, Cassiola F et al. Platelets actively sequester angiogenesis regulators. Blood 2009; 113: 2835-2842
  • 29 Park JE, Keller GA, Ferrara N. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell 1993; 4: 1317-1326
  • 30 Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 2001; 114: 853-865
  • 31 Jorgensen MC, Ahnfelt-Ronne J, Hald J et al. An illustrated review of early pancreas development in the mouse. Endocr Rev 2007; 28: 685-705
  • 32 De Leu N, Heremans Y, Coppens V et al. Short-term overexpression of VEGF-A in mouse beta cells indirectly stimulates their proliferation and protects against diabetes. Diabetologia 2013;