Abstract
AbstractWet age-related macular degeneration, which is characterized by choroidal neovascularization (CNV) and induces obvious vision loss. Vascular endothelial growth factor (VEGF) family member VEGF-A (also named as VEGF) and its receptor VEGFR2 contribute to the pathogenesis of CNV. Choroidal endothelial cells (CECs) secret C–C motif chemokine ligand 2 (CCL2), which attracts macrophages to CNV lesion and promotes macrophage M1 polarization. Accordingly, infiltrating macrophages secret inflammatory cytokines to promote CNV. In vivo, intravitreal injection of fruquintinib (HMPL-013), an antitumor neovascularization drug, alleviated mouse CNV formation without obvious ocular toxicity. Meanwhile, HMPL-013 inhibited VEGF/VEGFR2 binding in CECs and macrophages, as well as macrophage M1 polarization. In vitro, noncontact coculture of human choroidal vascular endothelial cells (HCVECs) and macrophages under hypoxia conditions was established. HMPL-013 downregulated VEGF/VEGFR2/phosphoinositide-3-kinase/protein kinase B (AKT)/nuclear factor kappa B pathway and CCL2 secretion in HCVECs, as well as VEGF/VEGFR2-induced macrophage M1 polarization under hypoxia condition. In addition, HMPL-013 inhibited HCEVC derived CCL2-induced macrophage migration and M1 polarization, along with macrophage M1 polarization-induced HCVECs proliferation, migration, and tube formation. Altogether, HMPL-013 alleviated CNV formation might via breaking detrimental cross talk between CECs and macrophages.
Funder
Suzhou Municipal Science and Technology Bureau
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
Reference41 articles.
1. Wong, W. L. et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health 2, e106–e116 (2014).
2. Li, J., Zhang, H., Sun, P., Gu, F. & Liu, Z. L. Bevacizumab vs ranibizumab for neovascular age-related macular degeneration in Chinese patients. Int J. Ophthalmol. 6, 169–173 (2013).
3. Eichler, W., Yafai, Y., Wiedemann, P. & Reichenbach, A. Angiogenesis-related factors derived from retinal glial (Muller) cells in hypoxia. Neuroreport 15, 1633–1637 (2004).
4. Liu, C. H., Wang, Z., Sun, Y. & Chen, J. Animal models of ocular angiogenesis: from development to pathologies. FASEB J. 31, 4665–4681 (2017).
5. Basavarajappa, H. D. et al. Ferrochelatase is a therapeutic target for ocular neovascularization. EMBO Mol. Med. 9, 786–801 (2017).
Cited by
13 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献