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Delta-like 4 inhibits choroidal neovascularization despite opposing effects on vascular endothelium and macrophages |
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| Authors: | 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 Florian Sennlaub |
| Institution: | 1. Centre de Recherche des Cordeliers, INSERM, UMR S 872, 75006, Paris, France 2. UPMC Univ Paris 06, UMR S 872, 75006, Paris, France 3. Université Paris Descartes, UMR S 872, 75006, Paris, France 4. ?Inflammation, dégénérescence et remodelage vasculaire dans les pathologies rétiniennes?, Institut de la Vision, INSERM UMRS 968, 17 rue Moreau, 75012, Paris, France 5. Institut de la Vision, UPMC Univ Paris 06, UMR_S 968, 75012, Paris, France 6. CNRS, UMR_7210, 75012, Paris, France 7. CIRB, Collège de France, CNRS UMR 7241/Inserm U1050, Paris, France 9. CEA Grenoble, DSV/iRTSV/BGE(INSERM U-1038)/Biomics, 17 rue des Martyrs, 38054, Grenoble, France 10. Plateforme d’imagerie, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S 872, Paris, France 11. Assistance Publique des H?pitaux de St Etienne, Centre hospitalier universitaire de Saint-Etienne, Université Jean Monnet; Faculté de Médecine, St Etienne, France 12. CIISA, Faculdade de Medicina Veterinária, Universidade Técnica de Lisboa, Avenida da Universidade Técnica, 1300-477, Lisbon, Portugal 13. Instituto Gulbenkian de Ciência, 2781-901, Oeiras, Portugal 8. Sisène; Paris Biotech Santé, Paris, France 14. H?tel-Dieu Hospital, Department of Ophthalmology, APHP, Paris, France 15. Equipe 14, Institut de la Vision, 17, rue Moreau, 75012, Paris, France |
| Abstract: | 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. |
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