RESUMO
AIMS/HYPOTHESIS: Vascular endothelial growth factor (VEGF) has been recognised by loss-of-function experiments as a pleiotropic factor with importance in embryonic pancreas development and postnatal beta cell function. Chronic, nonconditional overexpression of VEGF-A has a deleterious effect on beta cell development and function. We report, for the first time, a conditional gain-of-function study to evaluate the effect of transient VEGF-A overexpression by adult pancreatic beta cells on islet vasculature and beta cell proliferation and survival, under both normal physiological and injury conditions. METHODS: In a transgenicmouse strain, overexpressing VEGF-A in a doxycycline-inducible and beta cell-specific manner, we evaluated the ability of VEGF-A to affect islet vessel density, beta cell proliferation and protection of the adult beta cell mass from toxin-induced injury. RESULTS: Short-term VEGF-A overexpression resulted in islet hypervascularisation, increased beta cell proliferation and protection from toxin-mediated beta cell death, and thereby prevented the development of hyperglycaemia. Extended overexpression of VEGF-A led to impaired glucose tolerance, elevated fasting glycaemia and a decreased beta cell mass. CONCLUSIONS/INTERPRETATION: Overexpression of VEGF-A in beta cells time-dependently affects glycometabolic control and beta cell protection and proliferation. These data nourish further studies to examine the role of controlled VEGF delivery in (pre)clinical applications aimed at protecting and/or restoring the injured beta cell mass.
Assuntos
Diabetes Mellitus/prevenção & controle , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Proliferação de Células , Sobrevivência Celular/fisiologia , Diabetes Mellitus/metabolismo , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/metabolismo , Camundongos , Camundongos Transgênicos , Ratos , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
It is generally accepted that vascularization and oxygenation of pancreatic islets are essential for the maintenance of an optimal ß-cell mass and function and that signaling by vascular endothelial growth factor (VEGF) is crucial for pancreas development, insulin gene expression/secretion, and (compensatory) ß-cell proliferation. A novel mouse model was designed to allow conditional production of human sFlt1 by ß-cells in order to trap VEGF and study the effect of time-dependent inhibition of VEGF signaling on adult ß-cell fate and metabolism. Secretion of sFlt1 by adult ß-cells resulted in a rapid regression of blood vessels and hypoxia within the islets. Besides blunted insulin release, ß-cells displayed a remarkable capacity for coping with these presumed unfavorable conditions: even after prolonged periods of blood vessel ablation, basal and stimulated blood glucose levels were only slightly increased, while ß-cell proliferation and mass remained unaffected. Moreover, ablation of blood vessels did not prevent ß-cell generation after severe pancreas injury by partial pancreatic duct ligation or partial pancreatectomy. Our data thus argue against a major role of blood vessels to preserve adult ß-cell generation and function, restricting their importance to facilitating rapid and adequate insulin delivery.