2. Academic Validation
  3. Role of TLR4-MAP4K4 signaling pathway in models of oxygen-induced retinopathy

Role of TLR4-MAP4K4 signaling pathway in models of oxygen-induced retinopathy

  • FASEB J. 2019 Mar;33(3):3451-3464. doi: 10.1096/fj.201801086RR.
Wenwen Chen 1 2 3 4,  Juan Zhang 1 2 3 4,  Peijun Zhang 1 2 3 4,  Fangyuan Hu 1 2 3 4,  Tingting Jiang 1 2 3 4,  Junxiang Gu 1 2 3 4,  Qing Chang 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Ophthalmology and Vision Science, Eye and Ear, Nose and Throat Hospital, Fudan University, Shanghai, China.
  • 2 Key Laboratory of Myopia of National Health Commission, Fudan University, Shanghai, China.
  • 3 Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.
  • 4 Key Laboratory of Visual Impairment and Restoration of Shanghai, Shanghai, China.
PMID: 30475644 DOI: 10.1096/fj.201801086RR
Abstract

Retinopathy of prematurity is a vision-threatening condition, and therapies based on antagonizing VEGF may elicit serious side effects in premature infants. Mechanisms of retinal angiogenesis, particularly the signaling pathways independent of VEGF, remain elusive. The goals of our study were to explore TLR4-mediated signaling pathways in human retinal microvascular endothelial cells (HRMECs) and to examine the effects of TLR4 antagonists in models of oxygen-induced retinopathy (OIR). Our results show that intravitreal injection of the TLR4 Antagonist TAK-242 reduced areas of nonperfusion, inhibited aberrant angiogenesis, and improved vascular density in the retina of OIR mice. The effects were further potentiated by the anti-VEGF antibody ranibizumab. In cultured HRMECs, the TLR4 Agonist LPS up-regulated TLR4/MAPKK kinase kinase 4 (MAP4K4) signaling, and promoted cell proliferation and migration, and reduced barrier functions of the cells. Down-regulation of MAP4K4 in HRMECs abolished the proangiogenic effects by LPS. Our data suggest that the TLR4-MAP4K4 pathway can regulate retinal neovascularization via mechanisms independent of VEGF.-Chen, W., Zhang, J., Zhang, P., Hu, F., Jiang, T., Gu, J., Chang, Q. Role of TLR4-MAP4K4 signaling pathway in models of oxygen-induced retinopathy.

Keywords

VEGF; angiogenesis; retina.

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