Dataset Information

Conditional hypovascularization and hypoxia in islets do not overtly influence adult ?-cell mass or function.

ABSTRACT: It is generally accepted that vascularization and oxygenation of pancreatic islets are essential for the maintenance of an optimal ?-cell mass and function and that signaling by vascular endothelial growth factor (VEGF) is crucial for pancreas development, insulin gene expression/secretion, and (compensatory) ?-cell proliferation. A novel mouse model was designed to allow conditional production of human sFlt1 by ?-cells in order to trap VEGF and study the effect of time-dependent inhibition of VEGF signaling on adult ?-cell fate and metabolism. Secretion of sFlt1 by adult ?-cells resulted in a rapid regression of blood vessels and hypoxia within the islets. Besides blunted insulin release, ?-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 ?-cell proliferation and mass remained unaffected. Moreover, ablation of blood vessels did not prevent ?-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 ?-cell generation and function, restricting their importance to facilitating rapid and adequate insulin delivery.

SUBMITTER: D'Hoker J

PROVIDER: S-EPMC3837025 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Conditional hypovascularization and hypoxia in islets do not overtly influence adult β-cell mass or function.

D'Hoker Joke J De Leu Nico N Heremans Yves Y Baeyens Luc L Minami Kohtaro K Ying Cai C Lavens Astrid A Chintinne Marie M Stangé Geert G Magenheim Judith J Swisa Avital A Martens Geert G Pipeleers Daniel D van de Casteele Mark M Seino Susumo S Keshet Eli E Dor Yuval Y Heimberg Harry H

Diabetes 20130823 12

It is generally accepted that vascularization and oxygenation of pancreatic islets are essential for the maintenance of an optimal β-cell mass and function and that signaling by vascular endothelial growth factor (VEGF) is crucial for pancreas development, insulin gene expression/secretion, and (compensatory) β-cell proliferation. A novel mouse model was designed to allow conditional production of human sFlt1 by β-cells in order to trap VEGF and study the effect of time-dependent inhibition of V ...[more]

PMID: 23974922

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Project description:BackgroundPancreatic islets are heavily vascularized in vivo yet lose this vasculature after only a few days in culture. Determining how to maintain islet vascularity in culture could lead to better outcomes in transplanting this tissue for the treatment of type 1 diabetes as well as provide insight into the complex communication between beta-cells and endothelial cells (ECs). We previously showed that islet ECs die in part due to limited diffusion of serum albumin into the tissue. We now aim to determine the impact of hypoxia on islet vascularization.MethodsWe induced hypoxia in cultured mouse islets using the hypoxia mimetic cobalt chloride (100 ?M CoCl2). We measured the impact on islet metabolism (two-photon NAD(P)H and Rh123 imaging) and function (insulin secretion and survival). We also measured the impact on hypoxia related transcripts (HIF-1?, VEGF-A, PDK-1, LDHA, COX4) and confirmed increased VEGF-A expression and secretion. Finally, we measured the vascularization of islets in static and flowing culture using PECAM-1 immunofluorescence.ResultsCoCl2 did not induce significant changes in beta cell metabolism (NAD(P)H and Rh123), insulin secretion, and survival. Consistent with hypoxia induction, CoCl2 stimulated HIF-1?, PDK-1, and LDHA transcripts and also stimulated VEGF expression and secretion. We observed a modest switch to the less oxidative isoform of COX4 (isoform 1 to 2) and this switch was noted in the glucose-stimulated cytoplasmic NAD(P)H responses. EC morphology and survival were greater in CoCl2 treated islets compared to exogenous VEGF-A in both static (dish) and microfluidic flow culture.ConclusionsHypoxia induction using CoCl2 had a positive effect on islet EC morphology and survival with limited impact on beta-cell metabolism, function, and survival. The EC response appears to be due to endogenous production and secretion of angiogenic factors (e.g. VEGF-A), and mechanistically independent from survival induced by serum albumin.

Dataset Information

Conditional hypovascularization and hypoxia in islets do not overtly influence adult ?-cell mass or function.

Publications

Conditional hypovascularization and hypoxia in islets do not overtly influence adult β-cell mass or function.

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