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

Autor: Steve J Harper, David O. Bates, A Clark, Peter W. Mathieson, S. K. Richards, S E Cross, Paul R.V. Johnson, Andrew V. Benest, R. M. Smith
Jazyk: angličtina
Rok vydání: 2007
Předmět:
Vascular Endothelial Growth Factor A
medicine.medical_specialty
endocrine system
Edmonton protocol
endocrine system diseases
Cell Survival
Endocrinology
Diabetes and Metabolism
VEGF receptors
medicine.medical_treatment
Islets of Langerhans Transplantation
Islets of Langerhans
Mice
chemistry.chemical_compound
Neoplasms
Diabetes mellitus
Internal medicine
Internal Medicine
medicine
Animals
Humans
Cells
Cultured
Sirolimus
geography
geography.geographical_feature_category
Neovascularization
Pathologic
biology
business.industry
Immunosuppressive regimen
medicine.disease
Islet
Mice
Inbred C57BL
Transplantation
Vascular endothelial growth factor
Receptors
Vascular Endothelial Growth Factor
Endocrinology
chemistry
Cell culture
Cancer research
biology.protein
business
Immunosuppressive Agents
Signal Transduction
Zdroj: Diabetologia. 50(7)
ISSN: 1432-0428
0012-186X
Popis: 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 post-transplantation, both through a direct effect on islet viability and indirectly through blockade of VEGF-mediated revascularisation.
Databáze: OpenAIRE
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