title: Myeloid-Specific Blockade of Notch Signaling Attenuates Choroidal Neovascularization through Compromised Macrophage Infiltration and Polarization in Mice.
abstract: Macrophages have been recognized as an important inflammatory component in choroidal neovascularization (CNV). However, it is unclear how these cells are activated and polarized, how they affect angiogenesis and what the underlining mechanisms are during CNV. Notch signaling has been implicated in macrophage activation. Previously we have shown that inducible disruption of RBP-J, the critical transcription factor of Notch signaling, in adult mice results in enhanced CNV, but it is unclear what is the role of macrophage-specific Notch signaling in the development of CNV. In the current study, by using the myeloid specific RBP-J knockout mouse model combined with the laser-induced CNV model, we show that disruption of Notch signaling in macrophages displayed attenuated CNV growth, reduced macrophage infiltration and activation, and alleviated angiogenic response after laser induction. The inhibition of CNV occurred with reduced expression of VEGF and TNF-α in infiltrating inflammatory macrophages in myeloid specific RBP-J knockout mice. These changes might result in direct inhibition of EC lumen formation, as shown in an in vitro study. Therefore, clinical intervention of Notch signaling in CNV needs to pinpoint myeloid lineage to avoid the counteractive effects of global inhibition.
authors.affiliation: Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Guo-Rui
authors.initials: GR
authors.lastname: Dou
authors.affiliation: Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.|Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.|Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Tian-Fang
authors.initials: TF
authors.lastname: Chang
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xian-Chun
authors.initials: XC
authors.lastname: Yan
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China.|Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Wang
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D020256:Choroidal Neovascularization / Q000378:metabolism*; D004195:Disease Models, Animal; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A