Beta-Cell sparing in transplanted islets by vascular endothelial growth factor

Stagner, John I.; Mokshagundam, Sri Prakash L.; Wyler, Karen; Samols, Ellis; Rilo, Horacio; Stagner, M; Parthasarathy, Lathakumari; Parthasarathy, R.

doi:10.1016/j.transproceed.2004.04.036

Cited by 22 publications

(17 citation statements)

References 6 publications

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“…VEGF 165 may therefore have a double protective action by increasing islet survival early after transplantation and then promoting the revascularisation of those surviving islets. Studies of the effects of pretreatment of islets with VEGF have produced conflicting results [38,39], but we have demonstrated a beneficial effect of VEGF co-expression on transplanted islet survival in vivo. Glycaemic control was improved as early as day 1 post-transplantation, before the initiation of revascularisation, suggesting that VEGF may have a direct protective effect on islet viability that is independent of revascularisation.…”

Section: Discussionmentioning

confidence: 87%

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

et al. 2007

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Aims/hypothesis Rapamycin, part of the immunosuppressive regimen of the Edmonton protocol, has been shown to inhibit vascular endothelial growth factor (VEGF) production and VEGF-mediated survival signalling in tumour cell lines. This study investigates the survival-promoting activities of VEGF in human islets and the effects of rapamycin on islet viability.Materials and methods Levels of VEGF and its receptors in isolated human islets and whole pancreas was determined by western blotting and immunostaining. Islet viability following VEGF or immunosuppressive drug treatment was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Islet VEGF release was measured by ELISA. Mouse islets infected with an adenovirus expressing the gene for VEGF were transplanted syngeneically into streptozotocin-induced diabetic mice, with blood glucose levels measured three times per week. Results Isolated human islets produced multiple isoforms of VEGF and VEGF receptors 1, 2 and 3 and the coreceptor neuropilin 1. Exogenous VEGF (10 ng/ml) prevented human islet death induced by serum starvation, which suggests that VEGF can act as a survival factor for human islets. Transplantation of mouse islets infected with a VEGF-expressing adenovirus in a syngeneic model, improved glycaemic control at day 1 post-transplantation (p< 0.05). Rapamycin at 10 and 100 ng/ml significantly reduced islet VEGF release (by 37±4% and 43±6%, respectively; p<0.05) and at 100 ng/ml reduced islet viability (by 36±9%) and insulin release (by 47±7%, all vs vehicle-treated controls; p<0.05). Tacrolimus had no effect on islet VEGF release or viability. Conclusions/interpretation Our data suggest that rapamycin may have deleterious effects on islet survival posttransplantation, both through a direct effect on islet viability and indirectly through blockade of VEGF-mediated revascularisation.

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Section: Discussionmentioning

confidence: 87%

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

et al. 2007

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“…Moreover, the systemic concentration of VEGF was increased 2 days after pancreatectomy. VEGF is an important stimulator of islet angiogenesis [41,42]; it inhibits beta cell apoptosis and increases insulin secretion of transplanted islets [43]. VEGF has also been shown to mobilise endothelial progenitor cells [44], which increases revascularisation of transplanted islets [13].…”

Section: Discussionmentioning

confidence: 99%

Improved vascular engraftment and function of autotransplanted pancreatic islets as a result of partial pancreatectomy in the mouse and rat

2007

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Aims/hypothesis The few patients subjected to autotransplantation of pancreatic islets after pancreatectomy usually become normoglycaemic after using islets from the resected organ only, whereas allogeneic recipients usually require at least two grafts to retain normoglycaemia. Previous experimental studies have demonstrated that islets transplanted to non-pancreatectomised recipients acquire a markedly decreased blood vessel density, which leads to a hypoxic microenvironment. The aim of the present study was to test the hypothesis that autotransplanted islets have better vascular engraftment and function as a result of the pancreatic surgery involved. Materials and methods In the present study, athymic mice and inbred rats were subjected to a 60% pancreatectomy and transplanted with human or rat islets, respectively, 4 days later. Control animals underwent sham surgery. Blood flow, oxygen tension, vascular density and endocrine volume in the islet grafts were measured 1 month after transplantation. Separate grafts were used for perfusion experiments and for assessment of beta cell proliferation and endocrine cellular apoptosis at different time periods after transplantation.Results Islet grafts in partially pancreatectomised recipients had an increased blood flow, oxygen tension, blood vessel density and endocrine mass 1 month post-transplantation compared with control animals. They also exhibited increased insulin release in perfusion experiments performed 1 month post-transplantation, and decreased cellular apoptosis early after transplantation. Conclusions/interpretation The present study shows that the pancreatectomy procedure itself has beneficial effects on the engraftment of transplanted human and rat islets. Our results provide an additional explanation, besides diminished immunological responses, of the much better outcome of islet autotransplantations compared with allogeneic transplantations in the clinic.

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“…In our study, increased expression of IL-6 and MCP-1 in diabetic glomeruli was suppressed by antiangiogenic treatment, suggesting that the cytokines may mediate monocyte/macrophage infiltration. It has also been shown that VEGF increases the survival of pancreatic islets and thus beta cell sparing after islet transplantation by stimulating angiogenesis and improving islet revascularization [66, 67]. Moreover, transgenic mice that overexpress VEGF are characterized by islet hyperplasia, suggesting that VEGF modulates endocrine pancreatic differentiation [68].…”

Section: Pathogenesis Of Diabetic Nephropathymentioning

confidence: 99%

Recent Advancement of Understanding Pathogenesis of Type 1 Diabetes and Potential Relevance to Diabetic Nephropathy

Ichinose

Kawasaki²,

Eguchi³

2007

Am J Nephrol

102

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Type 1 diabetes mellitus is an autoimmune disease characterized by progressive destruction of pancreatic beta cells by genetic and environmental factors which leads to an absolute dependence of insulin for survival and maintenance of health. Although the majority of mechanisms of beta cell destruction remain unclear, many molecules, including proinflammatory cytokines and chemokines such as tumor necrosis factor alpha and monocyte chemoattractant protein-1, are implicated in the development of beta cell damage. Furthermore, beta cell destruction is enhanced by the Th1 and Th17 subsets of CD4+ T cells. In contrast, there are mechanisms involved in the maintenance of peripheral tolerance by regulatory T cells, the function of which depends on the pleiotropic cytokine transforming growth factor beta. Development and progression of renal injuries in patients with diabetic nephropathy are also associated with several growth factors and proinflammatory cytokines, including tumor necrosis factor alpha, insulin-like growth factor-1, monocyte chemoattractant protein-1, vascular endothelial growth factor, and transforming growth factor beta. Although the pathogenic mechanisms underlying type 1 diabetes and diabetic nephropathy are principally different, i.e., autoimmunity and inflammation, some common factors, including susceptibility genes and proinflammatory cytokines, are involved in both mechanisms, including infiltrating cell recruitment, upregulation of other cytokines and chemokines, or apoptosis.

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Beta-Cell sparing in transplanted islets by vascular endothelial growth factor

Cited by 22 publications

References 6 publications

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

Improved vascular engraftment and function of autotransplanted pancreatic islets as a result of partial pancreatectomy in the mouse and rat

Recent Advancement of Understanding Pathogenesis of Type 1 Diabetes and Potential Relevance to Diabetic Nephropathy

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