Reduced Insulin Secretion and Content in VEGF-A Deficient Mouse Pancreatic Islets

Jabs, Normund; Franklin, Isobel; Brenner, Martin; Gromada, Jesper; Ferrara, Napoleone; Wollheim, Claes B.; Lammert, Eckhard

doi:10.1055/s-2008-1081486

Cited by 34 publications

(31 citation statements)

References 9 publications

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“…6 Interestingly, mice deficient for VEGF-A in pancreatic islets have reduced insulin gene expression levels and impaired glucose tolerance. 30,31 In this regard, the capillary network is essential for fine-tuning blood glucose regulation, 32 suggesting that the angiostatic potential of CHOP-10 may participate in ␤-cell dysfunction under conditions of increased insulin demand. It is noteworthy that in our experimental conditions, the effect of CHOP-10 deficiency on postnatal vessel growth is not associated with changes in blood glucose levels.…”

Section: Discussionmentioning

confidence: 99%

C/EBP Homologous Protein-10 (CHOP-10) Limits Postnatal Neovascularization Through Control of Endothelial Nitric Oxide Synthase Gene Expression

et al. 2012

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Background— C/EBP homologous protein-10 (CHOP-10) is a novel developmentally regulated nuclear protein that emerges as a critical transcriptional integrator among pathways regulating differentiation, proliferation, and survival. In the present study, we analyzed the role of CHOP-10 in postnatal neovascularization. Methods and Results— Ischemia was induced by right femoral artery ligation in wild-type and CHOP-10 −/− mice. In capillary structure of skeletal muscle, CHOP-10 mRNA and protein levels were upregulated by ischemia and diabetes mellitus. Angiographic score, capillary density, and foot perfusion were increased in CHOP-10 −/− mice compared with wild-type mice. This effect was associated with a reduction in apoptosis and an upregulation of endothelial nitric oxide synthase (eNOS) levels in ischemic legs of CHOP-10 −/− mice compared with wild-type mice. In agreement with these results, eNOS mRNA and protein levels were significantly upregulated in CHOP-10 short interfering RNA–transfected human endothelial cells, whereas overexpression of CHOP-10 inhibited basal transcriptional activation of the eNOS promoter. Using a chromatin immunoprecipitation assay, we also showed that CHOP-10 was bound to the eNOS promoter. Interestingly, enhanced postischemic neovascularization in CHOP-10 −/− mice was fully blunted in CHOP-10/eNOS double-knockout animals. Finally, we showed that induction of diabetes mellitus is associated with a marked upregulation of CHOP-10 that substantially inhibited postischemic neovascularization. Conclusions— This study identifies CHOP-10 as an important transcription factor modulating vessel formation and maturation.

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Section: Discussionmentioning

confidence: 99%

C/EBP Homologous Protein-10 (CHOP-10) Limits Postnatal Neovascularization Through Control of Endothelial Nitric Oxide Synthase Gene Expression

et al. 2012

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“…These fenestrations are formed in response to the stimulus of vascular endothelial growth factor-A (VEGF-A) and angiopoietin-1 directly secreted by the islet cells. 6 On the other hand, endothelial cells secrete fibroblast growth factor-2 (FGF-2) and hepatocyte growth factor (HGF), which has a potent effect on b-cells enhancing their capacity to newly produce and secrete insulin glucose-responsiveness performance (Fig. 1).…”

Section: Cellular Structure and Interactions Of The Endothelium And Imentioning

confidence: 99%

“…Interventions with angiogenic factors, such as FGF-2, and VEGF accelerate the process attracting endothelial cells, to induce both proliferation and differentiation to produce a neovascular network at the transplantation site. 4,6,12 The intra-islet endothelial cells play a key role in the process of revascularization. However, those endothelial cells are particularly fragile and mostly disappear when islet are cultured after isolation.…”

Section: Revascularization Of Islet Grafts 29 the Role Of Vascular Enmentioning

confidence: 99%

“…[7][8][9][10] Furthermore, when knockout animals for VEGF-A or HGF are generated, they display abnormalities of the islet vessels, have impaired islet function and lose their glucosestimulated insulin secretion capacities. [6][7][8] The islets and endothelium has also several key interactions through the extracellular matrices (ECM) such collagen I, IV, laminin-1, fibronectin. These ECMs are capable to modulate important epigenetic changes, which include induction of insulin gene expression, stimulate b-cell replication and regulate the secretion of several paracrine factors (Fig.…”

Section: Cellular Structure and Interactions Of The Endothelium And Imentioning

confidence: 99%

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The role of endothelial cells on islet function and revascularization after islet transplantation

Toro-Arreola

Robles-Murillo²,

Daneri-Navarro

et al. 2016

Organogenesis

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“…Similarly, MSC-derived collagen IV binding to α1β1-integrin could stimulate insulin secretion [40]. Moreover, the release from BMderived cells of trophic molecules like HGF, IL-6, insulin-like growth factor binding proteins 4, VEGF A, and TGF-beta can directly sustain betacell survival and function [24, [41][42][43][44].…”

Section: Stem Cells Support Islet Graft By Increasing Tissue Revasculmentioning

confidence: 99%

Mesenchymal Stem Cells as Feeder Cells for Pancreatic Islet Transplants

Sordi¹,

Piemonti²

2010

Rev Diabet Stud

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■ AbstractAllogeneic islet transplant serves as a source for insulinsecreting beta-cells for the maintenance of normal glucose levels and treatment of diabetes. However, limited availability of islets, high rates of islet graft failure, and the need for life-long non-specific immunosuppressive therapy are major obstacles to the widespread application of this therapeutic approach. To overcome these problems, pancreatic islet transplantation was recently suggested as a potential target of the "therapeutic plasticity" of adult stem cells. In fact, new results suggest that stem/precursor cells, and mesenchymal stem cells in particular, co-transplanted with islets can promote tissue engraftment and beta-cell survival via bystander mechanisms, mainly exerted by creating a milieu of cytoprotective and immunomodulatory molecules. This evidence consistently challenges the limited view that stem/precursor cells work exclusively through beta-cell replacement in diabetes therapy. It proposes that stem cells also act as "feeder" cells for islets, and supporter of graft protection, tissue revascularization, and immune acceptance. This article reviews the experience of using stem cell co-transplantation as strategy to improve islet transplantation. It highlights that comprehension of the mechanisms involved will help to identify new molecular targets and promote development of new pharmacological strategies to treat type 1 and type 2 diabetes patients.

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Reduced Insulin Secretion and Content in VEGF-A Deficient Mouse Pancreatic Islets

Cited by 34 publications

References 9 publications

C/EBP Homologous Protein-10 (CHOP-10) Limits Postnatal Neovascularization Through Control of Endothelial Nitric Oxide Synthase Gene Expression

C/EBP Homologous Protein-10 (CHOP-10) Limits Postnatal Neovascularization Through Control of Endothelial Nitric Oxide Synthase Gene Expression

The role of endothelial cells on islet function and revascularization after islet transplantation

Mesenchymal Stem Cells as Feeder Cells for Pancreatic Islet Transplants

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