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Angiopoietin 2 Alters Pancreatic Vascularization in Diabetic Conditions 英文参考文献
Angiopoietin2AltersPancreaticVascularizationin
DiabeticConditions
SophieCalderari1*¤,Ce′cileChougnet1,MaudClemessy1,Herve′ Kempf1,2,PierreCorvol1 ,Etienne
Larger1,3
1INSERM U833, Colle`ge de France, Paris, France, 2Laboratoire de Physiopathologie, Pharmacologie et Inge′nierie Articulaires UMR 7561, CNRS-Nancy-Universite′,
Vandoeuvre-Le`s-Nancy,France,3Faculte′ deMe′decine,Universite′ ParisDescartes,Paris,France
Abstract
Aims/hypothesis:Isletvascularization,bycontrollingbeta-cellmassexpansioninresponsetoincreasedinsulindemand,is
implicated in the progression to glucose intolerance and type 2 diabetes. We investigated how hyperglycaemia impairs
expansionanddifferentiationofthegrowingpancreas.Wehavegraftedxenogenic(avian)embryonicpancreasinsevere
combined immuno-deficient (SCID) mouse and analyzed endocrine and endothelial development in hyperglycaemic
comparedtonormoglycaemicconditions.
Methods: 14dpi chicken pancreases were grafted under the kidney capsule of normoglycaemic or hyperglycaemic,
streptozotocin-induced, SCID mice and analyzed two weeks later. Vascularization was analyzed both quantitatively and
qualitatively using either in situ hybridization with both mouse- and chick-specific RNA probes for VEGFR2 or
immunohistochemistry with an antibody to nestin, a marker of endothelial cells that is specific for murine cells. To
inhibitangiopoietin2(Ang2),SCIDmiceweretreatedwith4mg/kgIPL1–10twice/week.
Results:Innormoglycaemiccondition,chicken-derivedendocrineandexocrinecellsdevelopedwellandintragraftvessels
werelinedwithmouseendothelialcells.Whenpancreasesweregraftedinhyperglycaemicmice,growthanddifferentiation
of the graft were altered and we observed endothelial discontinuities, large blood-filled spaces. Vessel density was
decreased. These major vascular anomalies were associated with strong over-expression of chick-Ang2. To explore the
possibility that Ang2 over-expression could be a key step in vascular disorganization induced by hyperglycaemia, we
tr
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