title: PEDF mediates pathological neovascularization by regulating macrophage recruitment and polarization in the mouse model of oxygen-induced retinopathy.
abstract: Macrophages have been demonstrated to play a proangiogenic role in retinal pathological vascular growth. Pigment epithelium-derived factor (PEDF) works as a powerful endogenous angiogenesis inhibitor, but its role in macrophage recruitment and polarization is largely unknown. To explore the underlying mechanisms, we first evaluated macrophage polarization in the retinas of the oxygen-induced retinopathy (OIR) mouse model. Compared to that in normal controls, M1- and M2-like macrophages were all abundantly increased in the retinas of OIR mice. In addition, both M1 and M2 subtypes significantly promoted neovascularization in vitro and in vivo. In addition, we found that PEDF inhibited retinal neovascularization by dampening macrophage recruitment and polarization. Furthermore, PEDF inhibited macrophage polarization through adipose triglyceride lipase (ATGL) by regulating the activation of MAPKs and the Notch1 pathway, as we found that the phosphorylation of MAPKs, including p38MAPK, JNK and ERK, as well as the accumulation of Notch1 were essential for hypoxia-induced macrophage polarization, while PEDF significantly dampened M1 subtype-related iNOS and M2 subtype-related Arg-1 expression by inhibiting hypoxia-induced activation of Notch1 and MAPKs through ATGL. These findings reveal a protective role of PEDF against retinal neovascularization by regulating macrophage recruitment and polarization.
authors.affiliation: Department of Ophthalmology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
authors.forename: Sha
authors.initials: S
authors.lastname: Gao
authors.affiliation: Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
authors.forename: Changwei
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
authors.forename: Yanji
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Ophthalmology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
authors.forename: Yanuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
authors.forename: Ailing
authors.initials: A
authors.lastname: Sui
authors.affiliation: Department of Ophthalmology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Ophthalmology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Ophthalmology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Shen
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D016764:Cell Polarity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008049:Lipase / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism*; D010100:Oxygen / Q000009:adverse effects*; D010766:Phosphorylation; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D015843:Serpins / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor; D000217:Acyltransferases
chemical_list: D005136:Eye Proteins; D008049:Lipase; D009414:Nerve Growth Factors; D010100:Oxygen; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C494794:PNPLA2 protein, human; D000217:Acyltransferases