title: Angiopoietin 2 alters pancreatic vascularization in diabetic conditions.
abstract: OBJECTIVE
  Islet vascularization, by controlling beta-cell mass expansion in response to increased insulin demand, is implicated in the progression to glucose intolerance and type 2 diabetes. We investigated how hyperglycaemia impairs expansion and differentiation of the growing pancreas. We have grafted xenogenic (avian) embryonic pancreas in severe combined immuno-deficient (SCID) mouse and analyzed endocrine and endothelial development in hyperglycaemic compared to normoglycaemic conditions.
  
  
  METHODS
  14 dpi 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 inhibit angiopoietin 2 (Ang2), SCID mice were treated with 4 mg/kg IP L1-10 twice/week.
  
  
  RESULTS
  In normoglycaemic condition, chicken-derived endocrine and exocrine cells developed well and intragraft vessels were lined with mouse endothelial cells. When pancreases were grafted in hyperglycaemic mice, growth and differentiation 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 treated mice with L1-10, an Ang-2 specific inhibitor. Inhibition of Ang2 improved vascularization and beta-cell density.
  
  
  CONCLUSIONS
  This work highlighted an important role of Ang2 in pancreatic vascular defects induced by hyperglycaemia.
authors.affiliation: INSERM U833, Collège de France, Paris, France. sophie.calderari@crc.jussieu.fr
authors.forename: Sophie
authors.initials: S
authors.lastname: Calderari
authors.forename: Cécile
authors.initials: C
authors.lastname: Chougnet
authors.forename: Maud
authors.initials: M
authors.lastname: Clemessy
authors.forename: Hervé
authors.initials: H
authors.lastname: Kempf
authors.forename: Pierre
authors.initials: P
authors.lastname: Corvol
authors.forename: Etienne
authors.initials: E
authors.lastname: Larger
mesh_terms: D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002642:Chick Embryo; D002645:Chickens; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000098:blood supply / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D010179:Pancreas / Q000098:blood supply* / Q000378:metabolism; D016035:Pancreas Transplantation / Q000379:methods; D046790:Pancreas, Exocrine / Q000098:blood supply / Q000378:metabolism; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D001786:Blood Glucose; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2