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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

By Serge Camelo, William Raoul, Sophie Lavalette, Bertrand Calippe, Brunella Cristofaro, Olivier Levy, Marianne Houssier, Eric Sulpice, Laurent Jonet, Christophe Klein, Estelle Devevre, Gilles Thuret, Antonio Duarte, Anne Eichmann, Laurence Leconte, Xavier Guillonneau and Florian Sennlaub

Abstract

International audienceInflammatory 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

Topics: Angiogenesis, Notch, DLL4, eye, age related macular degeneration, macrophages, MESH : Animals, MESH : Base Sequence, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH : Blotting, Western, MESH : Choroidal Neovascularization, MESH : DNA Primers, MESH : Endothelium, Vascular, MESH : Intercellular Signaling Peptides and Proteins, MESH : Macrophages, Peritoneal, MESH : Mice, MESH : Mice, Inbred C57BL, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.MHEP.OS ] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology
Publisher: Springer Verlag
Year: 2012
DOI identifier: 10.1007/s10456-012-9290-0
OAI identifier: oai:HAL:inserm-00853034v1
Provided by: Hal-Diderot

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