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Endothelial AGGF1 promotes retinal angiogenesis by coordinating TNFSF12/FN14 signalling

Author

Listed:
  • Ying Cheng

    (Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology)

  • Man Zhang

    (Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology)

  • Chenguang Li

    (Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology)

  • Long Su

    (Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology
    The Second Hospital of Tianjin Medical University)

  • Lingli Fu

    (Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology)

  • Shi Wu

    (Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology)

  • Chaofei Xu

    (Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology)

  • Bei Sun

    (Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology)

  • Liming Chen

    (Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology)

Abstract

Abnormal angiogenesis is a key process associated with ischaemic retinopathies such as diabetic retinopathy, for which the underlying pathological mechanisms are still poorly understood. Here, we confirm that angiogenic factor 1 with a G patch and FHA domain (AGGF1) is elevated in the diabetics and induces retinal angiogenesis. Mechanistic investigations demonstrate that HIF-1α directly regulates AGGF1 expression. AGGF1 upregulates the expression of cell cycle proteins by increasing the binding of tumour necrosis factor ligand superfamily member 12 (TNFSF12) to fibroblast -growth -factor-inducible 14 (FN14, TNFRSF12A). Furthermore, targeting AGGF1 attenuates pathological neovascularisation in ischaemic retinopathy. Additionally, we discover that sodium-glucose cotransporter 2 inhibitors (SGLT2i) could inhibit the AGGF1 signalling pathway early to achieve therapeutic effects. Overall, we elucidate the mechanism underlying pathological retinal angiogenesis involved in endothelial AGGF1-dependent events and highlight a therapy for the effective treatment of ischaemic retinopathy.

Suggested Citation

  • Ying Cheng & Man Zhang & Chenguang Li & Long Su & Lingli Fu & Shi Wu & Chaofei Xu & Bei Sun & Liming Chen, 2025. "Endothelial AGGF1 promotes retinal angiogenesis by coordinating TNFSF12/FN14 signalling," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55970-3
    DOI: 10.1038/s41467-025-55970-3
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    References listed on IDEAS

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    1. Xiao-Li Tian & Rajkumar Kadaba & Sun-Ah You & Mugen Liu & Ayse Anil Timur & Lin Yang & Qiuyun Chen & Przemyslaw Szafranski & Shaoqi Rao & Ling Wu & David E. Housman & Paul E. DiCorleto & David J. Dris, 2004. "Identification of an angiogenic factor that when mutated causes susceptibility to Klippel–Trenaunay syndrome," Nature, Nature, vol. 427(6975), pages 640-645, February.
    2. Meng-Lin Chao & Shanshan Luo & Chao Zhang & Xuechun Zhou & Miao Zhou & Junyan Wang & Chuiyu Kong & Jiyu Chen & Zhe Lin & Xin Tang & Shixiu Sun & Xinlong Tang & Hongshan Chen & Hong Wang & Dongjin Wang, 2021. "S-nitrosylation-mediated coupling of G-protein alpha-2 with CXCR5 induces Hippo/YAP-dependent diabetes-accelerated atherosclerosis," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
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