Angiopoietin 2 Alters Pancreatic Vascularization in Diabetic Conditions

Caldérari, Sophie; Chougnet, C.; Clemessy, Maud; Kempf, Hervé; Corvol, Pierre; Larger, Étienne

doi:10.1371/journal.pone.0029438

Cited by 16 publications

(12 citation statements)

References 59 publications

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“…It is possible that hyperglycaemia prolongs the inflammatory changes of the exocrine pancreas elicited by the M3Cherry injection. In support of this theory, hyperglycaemia has been linked to impaired exocrine regeneration [40, 41] and impaired wound healing [42]. We found high expression of HSP60 in tubular complexes.…”

Section: Discussionsupporting

confidence: 79%

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice

Cavelti-Weder

Zumsteg

et al. 2015

Diabetologia

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Aims/hypothesis Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined. Methods Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors. Results We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue’s response to clear the pancreas from insufficiently reprogrammed cells. Conclusions/interpretation Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications.

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Section: Discussionsupporting

confidence: 79%

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice

Cavelti-Weder

Zumsteg

et al. 2015

Diabetologia

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“…For example, some, but not all studies reported that angiopoietins have a role in islet vascularization212223. We thus quantified the mRNA levels of Angiopoietin-1 and Angiopoietin-2, but did not detect any difference between control and ILK cKO islets either (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 91%

The biomechanical properties of an epithelial tissue determine the location of its vasculature

et al. 2016

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An important question is how growing tissues establish a blood vessel network. Here we study vascular network formation in pancreatic islets, endocrine tissues derived from pancreatic epithelium. We find that depletion of integrin-linked kinase (ILK) in the pancreatic epithelial cells of mice results in glucose intolerance due to a loss of the intra-islet vasculature. In turn, blood vessels accumulate at the islet periphery. Neither alterations in endothelial cell proliferation, apoptosis, morphology, Vegfa expression and VEGF-A secretion nor ‘empty sleeves' of vascular basement membrane are found. Instead, biophysical experiments reveal that the biomechanical properties of pancreatic islet cells, such as their actomyosin-mediated cortex tension and adhesive forces to endothelial cells, are significantly changed. These results suggest that a sorting event is driving the segregation of endothelial and epithelial cells and indicate that the epithelial biomechanical properties determine whether the blood vasculature invades or envelops a growing epithelial tissue.

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“…Hyperglycemia and free fatty acids ablate Ang-1 mediated Tie-2 signaling in HUVECs [ 31 ] whereas Ang-1 protects islets from cytokine induced apoptosis also in absence of Tie-2 and improves islet revascularization post-transplantation [ 32 ]. In contrast, Ang-2 has been associated with vascular defects under hyperglycemia [ 33 ]. While VEGF-A overexpression increased vascularization near the islet cells and massively altered β-cell function, proliferation and mass, β-cell specific overexpression of Ang-1 or Ang-2 only slightly impaired insulin secretion and glucose tolerance together with marginal altered vascularization, islet mass and morphology [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Angiopoetin-2 Signals Do Not Mediate the Hypervascularization of Islets in Type 2 Diabetes

et al. 2016

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AimsChanges in the islet vasculature have been implicated in the regulation of β-cell survival and function during the progression to type 2 diabetes (T2D). Failure of the β-cell to compensate for the increased insulin demand in obesity eventually leads to diabetes; as a result of the complex interplay of genetic and environmental factors (e.g. ongoing inflammation within the islets) and impaired vascular function. The Angiopoietin/Tie (Ang/Tie) angiogenic system maintains vasculature and is closely related to organ inflammation and angiogenesis. In this study we aimed to identify whether the vessel area within the islets changes in diabetes and whether such changes would be triggered by the Tie-antagonist Ang-2.MethodsImmunohistochemical and qPCR analyses to follow islet vascularization and Ang/Tie levels were performed in human pancreatic autopsies and isolated human and mouse islets. The effect of Ang-2 was assessed in β-cell-specific Ang-2 overexpressing mice during high fat diet (HFD) feeding.ResultsIslet vessel area was increased in autopsy pancreases from patients with T2D. The vessel markers Tie-1, Tie-2 and CD31 were upregulated in mouse islets upon HFD feeding from 8 to 24 weeks. Ang-2 was transiently upregulated in mouse islets at 8 weeks of HFD and under glucolipotoxic conditions (22.2 mM glucose/ 0.5 mM palmitate) in vitro in human and mouse islets, in contrast to its downregulation by cytokines (IL-1β, IFN-ɣ and TNF-α). Ang-1 on the other hand was oppositely regulated, with a significant loss under glucolipotoxic condition, a trend to reduce in islets from patients with T2D and an upregulation by cytokines. Modulation of such changes in Ang-2 by its overexpression or the inhibition of its receptor Tie-2 impaired β-cell function at basal conditions but protected islets from cytokine induced apoptosis. In vivo, β-cell-specific Ang-2 overexpression in mice induced hypervascularization under normal diet but contrastingly led to hypovascularized islets in response to HFD together with increased apoptosis and reduced β-cell mass.ConclusionsIslet hypervascularization occurs in T2D. A balanced expression of the Ang1/Ang2 system is important for islet physiology. Ang-2 prevents β-cell mass and islet vascular adaptation in response to HFD feeding with no major influence on glucose homeostasis.

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Angiopoietin 2 Alters Pancreatic Vascularization in Diabetic Conditions

Cited by 16 publications

References 59 publications

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice

The biomechanical properties of an epithelial tissue determine the location of its vasculature

Angiopoetin-2 Signals Do Not Mediate the Hypervascularization of Islets in Type 2 Diabetes

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