April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Role of Endothelial Cell Adam-10 In Murine Developmental Angiogenesis and Proliferative Retinopathies
Author Affiliations & Notes
  • Krzysztof Glomski
    Biochemisty and Cell Biology, Weill Cornell Medical College, New York, New York
  • Paul Saftig
    Biochemistry, Christian Albrecht University, Kiel, Germany
  • Bart de Strooper
    VIB and KU, Leuven, Belgium
  • Carl Blobel
    Biochemisty and Cell Biology, Weill Cornell Medical College, New York, New York
    Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 4833. doi:
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      Krzysztof Glomski, Paul Saftig, Bart de Strooper, Carl Blobel; Role of Endothelial Cell Adam-10 In Murine Developmental Angiogenesis and Proliferative Retinopathies. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4833.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : ADAMs (a disintegrin and metalloprotease) comprise a family of membrane anchored metalloproteases that cleave the extracellular domains of transmembrane proteins in a process termed ectodomain shedding, which is critical in the activation of numerous signaling pathways. In the developing retina, Notch-1 negatively regulates vascular branching. Based on previous studies reporting ADAM10 as the likely metalloprotease responsible for activating Notch-1, we hypothesized that deletion of ADAM10 from endothelial cells (ECs) would increase vascular branching during developmental angiogenesis and proliferative retinopathy.

Methods: : Endothelial cell specific Tie2-cre mice were bred to animals carrying Adam10flox alleles to generate mice lacking Adam10 in ECs (A10ΔEC). Developmental angiogenesis in day 5 retinae was assessed via measurement of EC density and vascular branching in retinal whole mounts. To assess pathological neovascularization, mice were subjected to oxygen induced retinopathy (75% oxygen for 5 days starting at postnatal day 7, followed by 21% oxygen for an additional 5 days) and then the development of neovascular tufts and the size of the central avascular area was measured.

Results: : A10ΔEC mice displayed increased vascular density and greater vascular branching during developmental angiogenesis. Moreover, we observed fuller revascularization in the oxygen induced retinopathy model, and development of large neovascular tufts above the internal limiting membrane in A10ΔEC mice.

Conclusions: : These studies demonstrate that endothelial ADAM10 regulates vascular branching in developing retinae, likely through activating Notch signaling in immature ECs and suppressing their differentiation into ‘tip cells’ capable of forming new vascular branch points. ADAM10 in endothelial cells also negatively regulates pathological neovascularization and should therefore be considered an anti-target in metalloprotease-based anti-angiogenic interventions for proliferative retinopathies.

Keywords: retinal development • retinal neovascularization 
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