Journal Article

PSF functions as a repressor of hypoxia-induced angiogenesis by promoting mitochondrial function

Li, Xiaorong, Dong, Lijie, Hong, Yaru, Liu, Boshi, Zhang, Xiaomin, Lin, Tingting, Li, Wenbo

2021

Overview

Background Abnormal neovascularization is the most common cause of blindness, and hypoxia alters tissue metabolism, function, and morphology. HIF-1α, the transcriptional activator of VEGF, has intricate mechanisms of nuclear translocation and activation, but its signal termination mechanisms remain unclear. Methods We investigated the role of polypyrimidine tract-binding protein-associated splicing factor (PSF) in cellular energy production, migration, and proliferation by targeting HIF-1α in vivo and in vitro PSF plasmids were transfected with liposome 2000 transfection reagent. Young C57/BL6J mice were kept in a hyperoxia environment, followed by indoor air, resulting in oxygen-induced retinopathy. Oxygen-induced retinopathy (OIR) animals were randomly divided into three groups: OIR group, OIR + vector group (OIR cubs treated with rAAV vector) and OIR + PSF group (OIR cubs treated with rAAV-PSF). Age-matched C57/BL6J mice were used as controls and exposed to constant normoxic conditions. The animals were executed and their pupils were subjected to subsequent experiments. The metabolic spectrum was analyzed by Seahorse XFe96 flux analyzer, and OCR and extracellular acidification rate were quantified at the same time. Results PSF ameliorated retinal neovascularization and corrected abnormal VEGF expression in mice with oxygen-induced retinopathy and reduced intra-retinal neovascularization in Vldlr − / − mice. PSF reprogrammed mitochondrial bioenergetics and inhibited the transition of endothelial cells after hypoxia, suggesting its involvement in pathological angiogenesis.Ectopic PSF expression inhibited hypoxia-induced HIF-1α activation in the nucleus by recruiting Hakai to the PSF/HIF-1α complex, causing HIF-1α inhibition. PSF knockdown increased hypoxia-stimulated HIF-1α reactions. These hypoxia-dependent processes may play a vital role in cell metabolism, migration, and proliferation. Thus, PSF is a potential treatment target in neovascularization-associated ophthalmopathy. Conclusion This is the first study showing that PSF inhibits HIF-1α via recruitment of Hakai, modulates mitochondrial oxidation and glycolysis, and downregulates VEGF expression under hypoxia. We propose a new HIF-1 α/Hakai regulatory mechanism that may play a vital role in the pathogenesis of neovascularization in ophthalmopathy. PSF-Hakai–HIF-1α signaling pathway under hypoxia condition. Schematic diagram showing that the PSF-Hakai–HIF-1α signaling pathway. Under hypoxia condition, PSF-Hakai complex regulate HIF-1α signaling, thus inhibiting downstream target gene VEGF, cell metabolism and angiogenesis eventually. Bpb6gLDdM8K1hTjkEP-G9v Video Abstract: Detailed information of Materials and Methods.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Acidification / Angiogenesis / Animals / Antibodies / Bioenergetics / Biomedical and Life Sciences / Blindness / Cell Biology / Cell growth / Cell migration / Cell Movement / Cells, Cultured / Cytokines and Growth Factors / Endothelial cells / Endothelial Cells - metabolism / Endothelial Cells - physiology / Genes / Glycolysis / Hakai / HIF1-α / Humans / Hyperoxia / Hypoxia / Hypoxia - complications / Hypoxia - genetics / Hypoxia - metabolism / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Hypoxia-inducible factor 1a / Life Sciences / Metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Mitochondria / Mitochondria - metabolism / Neovascularization / Nuclear transport / Oxidation / Oxygen / Phosphorylation / Plasmids / Polypyrimidine tract-binding protein / Protein-Ligand Interactions / Proteins / PSF / PTB-Associated Splicing Factor - genetics / PTB-Associated Splicing Factor - metabolism / Quantitative analysis / Receptors / Receptors, LDL - genetics / Respiration / Retina / Retina - metabolism / Retinal Diseases - etiology / Retinal Diseases - genetics / Retinal Diseases - metabolism / Retinopathy / Signal transduction / Splicing factors / Transcription / Transfection / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - genetics / Vascular Endothelial Growth Factor A - metabolism / Vascularization / VEGF