PGF2α facilitates pathological retinal angiogenesis by modulating endothelial FOS-driven ELR+ CXC chemokine expression

  • EMBO Mol Med. 2022 Dec 13;e16373. doi: 10.15252/emmm.202216373.
Yan Zhao  1  2 ,  Yi Lei  #  3 ,  Huying Ning  #  1 ,  Yaqiang Zhang  4 ,  Guilin Chen  1 ,  Chenchen Wang  1  2 ,  Qiangyou Wan  2 ,  Shumin Guo  1 ,  Qian Liu  1 ,  Ruotian Xie  1 ,  Yujuan Zhuo  1 ,  Shuai Yan  2 ,  Jing Zhao  5 ,  Fengjiang Wei  5 ,  Lu Wang  1 ,  Xiaohong Wang  1 ,  Weidong Li  5 ,  Hua Yan  3 ,  Ying Yu  1
Affiliations
  • 1. Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China.
  • 2. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 3. Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, China.
  • 4. Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai, China.
  • 5. Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • # Contributed equally.
PMID: 36511116 DOI: 10.15252/emmm.202216373
Abstract

The pathological retinal angiogenesis often causes blindness. Current anti-angiogenic therapy for proliferative retinopathy targets the vascular endothelial growth factor (VEGF), but many patients do not radically benefit from this therapy. Herein, we report that circulating prostaglandin (PG) F2α metabolites were increased in type 2 diabetic patients with proliferative retinopathy, and the PGF2α receptor (Ptgfr) was upregulated in retinal endothelial cells (ECs) from a mouse model of oxygen-induced retinopathy (OIR). Further, disruption of the PTGFR receptor in ECs attenuated OIR in mice. PGF2α promoted the proliferation and tube formation of human retinal microvascular endothelial cells (HRMECs) via the release of ELR+ CXC Chemokines, such as CXCL8 and CXCL2. Mechanistically, the PGF2α /PTGFR axis potentiated ELR+ CXC chemokine expression in HRMECs through the Gq /CAMK2G/p38/ELK-1/FOS pathway. Upregulated FOS-mediated ELR+ CXC chemokine expression was observed in retinal ECs from PDR patients. Moreover, treatment with PTGFR inhibitor lessened the development of OIR in mice in a CXCR2-dependent manner. Therefore, inhibition of PTGFR may represent a new avenue for the treatment of retinal neovascularization, particularly in PDR.

Keywords
PGF2α; anti-angiogenic therapy; pathological retinal angiogenesis.
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