DDR2 alleviates retinal vaso-obliteration and pathological neovascularization by modulating microglia M1/M2
Qinjin Dai1, Wenqi Su1, Zhongcheng Zhou1
1Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
Insights
Discoidin domain receptor 2 (DDR2) shows promise for treating retinopathy of prematurity (ROP). Early DDR2 upregulation reduces retinal damage and promotes vascular maturation by modulating microglia and the STAT6/TGF-β pathway.
Area of Science:
- Ophthalmology
- Developmental Biology
- Molecular Medicine
Background:
- Retinopathy of prematurity (ROP) is a major cause of infant blindness.
- Current ROP treatments target late stages and have side effects.
- The role of discoidin domain receptor 2 (DDR2) in ROP is unknown.
Purpose of the Study:
- Investigate the role of DDR2 in retinopathy of prematurity (ROP).
- Elucidate the underlying mechanisms of DDR2's action in ROP.
- Explore DDR2 as a potential therapeutic target for ROP.
Main Methods:
- Utilized a mouse oxygen-induced retinopathy (OIR) model.
- Assessed DDR2 expression during retinal vascular development and OIR.
- Examined the effects of early DDR2 upregulation on retinal neovascularization and vascular maturation.
- Analyzed microglia polarization and the STAT6/TGF-β signaling pathway.
Main Results:
- DDR2 expression varied during physiological and pathological retinal vascularization in OIR.
- Early DDR2 upregulation attenuated retinal vaso-obliteration and pathological neovascularization.
- DDR2 promoted retinal vascular maturation and increased M2-polarized microglia.
- DDR2 activated the STAT6/TGF-β signaling pathway.
Conclusions:
- DDR2 plays a protective role in oxygen-induced retinopathy (OIR).
- DDR2 inhibits pathological neovascularization by promoting M2 microglia polarization via the STAT6/TGF-β pathway.
- DDR2 represents a potential early therapeutic target for retinopathy of prematurity (ROP).
Abstract:
Retinopathy of prematurity (ROP), a leading cause of blindness in premature infants, is characterized by retinal vaso-obliteration during hyperoxia and pathological neovascularization (NV) in relative hypoxia phase. Current treatments, which focus on the late stages of pathological neovascularization, are associated with numerous side effects. Studies demonstrated that discoidin domain receptor 2 (DDR2), a collagen-binding receptor tyrosine kinase, inhibits the experimental choroidal neovascularization and participates in tumor angiogenesis. However, the role of DDR2 in ROP and underlying mechanisms is unclear. In this study, we initially found that DDR2 expressed during mouse physiological retinal vascular development and significantly decreased in vaso-obliteration phase followed by increase during pathological neovascularization phase in mouse oxygen-induced retinopathy (OIR) model. Early upregulation of DDR2 before hyperoxia attenuates oxygen-induced vaso-obliteration, reduces pathological neovascularization, and promotes retinal vascular maturation. Additionally, DDR2 upregulation increased the number of microglia around retinal blood vessels and induced anti-inflammatory M2 polarization. Furthermore, the STAT6/TGF-β signaling pathway suppressed during hyperoxia was activated after DDR2 upregulation. In conclusion, DDR2 attenuated vaso-obliteration and inhibited pathological neovascularization by switching the microglia polarization from M1 to M2 phenotype via the STAT6/TGF-β signaling pathway in OIR. This suggests that DDR2 could be a novel target for the early treatment of ROP.
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