title: The anti-angiogenic role of discoidin domain receptor 2 (DDR2) in laser-induced choroidal neovascularization.
abstract: Choroidal neovascularization (CNV), an aberrant growth of blood vessels in the choroid layer of the eye, is a major cause of vision loss. In view of our recent finding that discoidin domain receptor 2 (DDR2), a collagen-binding receptor tyrosine kinase, is involved in control of vascular endothelial activity and tumor angiogenesis, the present study aims to investigate whether and how DDR2 affects the pathogenesis of CNV. We initially found that a spontaneous DDR2 mutant mouse colony (slie) exhibited enhanced amplitude of laser-induced CNV. The inhibitory role of DDR2 in CNV development was further confirmed by experiments through intravitreous injection of DDR2 small interference RNA (siRNA) or DDR2-expressing adenovirus. Quantitative real-time polymerase chain reaction (qPCR) and immunoblot analysis showed that DDR2 regulates the expression of several major pro-angiogenic factors in the laser-injured choroid as well as in retinal pigment epithelium (RPE) cells. In addition, it was demonstrated that the CNV-induced increases in the phosphorylation levels of Akt and mTOR were affected by the upregulation or downregulation of DDR2. Thus, the data from this study for the first time revealed that DDR2 negatively regulates the development of experimental CNV in vivo, which may provide a novel target for preventing human pathological ocular neovascularization. Key messages: DDR2 does not affect retinal development. DDR2 inhibits laser-induced CNV. DDR2 regulates angiogenic factor expression in CNV lesion as well as in RPE cells. DDR2 is involved in modulation of CNV-induced activation of PI3K pathway.
authors.affiliation: Department of Ophthalmology, Xijing Hospital, The Fourth Military Medical University, 169 Changle Western Road, Xi'an, 710032, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Xin
authors.initials: X
authors.lastname: Bu
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.forename: Shuya
authors.initials: S
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chang
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Su
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D020256:Choroidal Neovascularization / Q000209:etiology* / Q000473:pathology* / Q000628:therapy; D000070818:Discoidin Domain Receptors; D004195:Disease Models, Animal; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007834:Lasers / Q000009:adverse effects*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011975:Receptors, Mitogen / Q000235:genetics*; D015398:Signal Transduction; D014161:Transduction, Genetic
chemical_list: D034741:RNA, Small Interfering; D011975:Receptors, Mitogen; D019869:Phosphatidylinositol 3-Kinases; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases