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Delta-like 4 inhibits choroidal neovascularization despite opposing effects on vascular endothelium and macrophages. : DLL4's opposing effects in choroidal neovascularization
- Source :
- Angiogenesis, Angiogenesis, Springer Verlag, 2012, 15 (4), pp.609-22. 〈10.1007/s10456-012-9290-0〉, Angiogenesis, Springer Verlag, 2012, 15 (4), pp.609-22. ⟨10.1007/s10456-012-9290-0⟩, Angiogenesis, 2012, 15 (4), pp.609-22. ⟨10.1007/s10456-012-9290-0⟩
- Publication Year :
- 2012
- Publisher :
- HAL CCSD, 2012.
-
Abstract
- International audience; Inflammatory neovascularization, such as choroidal neovascularization (CNV), occur in the presence of Notch expressing macrophages. DLL4s anti-angiogenic effect on endothelial cells (EC) has been widely recognized, but its influence on Notch signaling on macrophages and its overall effect in inflammatory neovascularization is not well understood. We identified macrophages and ECs as the main Notch 1 and Notch 4 expressing cells in CNV. A soluble fraction spanning Ser28-Pro525 of the murine extracellular DLL4 domain (sDLL4/28-525) activated the Notch pathway, as it induces Notch target genes in macrophages and ECs and inhibited EC proliferation and vascular sprouting in aortic rings. In contrast, sDLL4/28-525 increased pro-angiogenic VEGF, and IL-1β expression in macrophages responsible for increased vascular sprouting observed in aortic rings incubated in conditioned media from sDLL4/28-525 stimulated macrophages. In vivo, Dll4(+/-) mice developed significantly more CNV and sDLL4/28-525 injections inhibited CNV in Dll4(+/-) CD1 mice. Similarly, sDLL4/28-525 inhibited CNV in C57Bl6 and its effect was reversed by a γ-secretase inhibitor that blocks Notch signaling. The inhibition occurred despite increased VEGF, IL-1β expression in infiltrating inflammatory macrophages in sDLL4/28-525 treated mice and might be due to direct inhibition of EC proliferation in laser-induced CNV as demonstrated by EdU labelling in vivo. In conclusion, Notch activation on macrophages and ECs leads to opposing effects in inflammatory neovascularization in situations such as CNV.
- Subjects :
- MESH: DNA Primers
Notch
genetic structures
age related macular degeneration
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
MESH : Blotting, Western
MESH : Mice, Inbred C57BL
MESH: Base Sequence
DLL4
MESH: Mice, Inbred C57BL
MESH: Reverse Transcriptase Polymerase Chain Reaction
MESH : Mice
MESH: Blotting, Western
MESH: Animals
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
[SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs
MESH: Intercellular Signaling Peptides and Proteins
MESH: Mice
[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology
MESH : Intercellular Signaling Peptides and Proteins
MESH : Choroidal Neovascularization
[ SDV.BC ] Life Sciences [q-bio]/Cellular Biology
MESH: Choroidal Neovascularization
MESH : Reverse Transcriptase Polymerase Chain Reaction
eye
eye diseases
macrophages
MESH : Endothelium, Vascular
MESH : Macrophages, Peritoneal
[ SDV.MHEP.OS ] Life Sciences [q-bio]/Human health and pathology/Sensory Organs
MESH : Base Sequence
MESH : DNA Primers
MESH: Endothelium, Vascular
sense organs
Angiogenesis
MESH : Animals
MESH: Macrophages, Peritoneal
Subjects
Details
- Language :
- English
- ISSN :
- 09696970 and 15737209
- Database :
- OpenAIRE
- Journal :
- Angiogenesis, Angiogenesis, Springer Verlag, 2012, 15 (4), pp.609-22. 〈10.1007/s10456-012-9290-0〉, Angiogenesis, Springer Verlag, 2012, 15 (4), pp.609-22. ⟨10.1007/s10456-012-9290-0⟩, Angiogenesis, 2012, 15 (4), pp.609-22. ⟨10.1007/s10456-012-9290-0⟩
- Accession number :
- edsair.dedup.wf.001..7a1296bddd3e09d63814c30ccb99a8ae