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

Background: Abnormal neovascularization is the most common cause of blindness, and hypoxia alters tissue metabolism, function, and morphology. HIF-1 alpha, 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-1 alpha 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-1 alpha activation in the nucleus by recruiting Hakai to the PSF/HIF-1 alpha complex, causing HIF-1 alpha inhibition. PSF knockdown increased hypoxia-stimulated HIF-1 alpha 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-1 alpha via recruitment of Hakai, modulates mitochondrial oxidation and glycolysis, and downregulates VEGF expression under hypoxia. We propose a new HIF-1 alpha/Hakai regulatory mechanism that may play a vital role in the pathogenesis of neovascularization in ophthalmopathy. PSF-Hakai-HIF-1 alpha signaling pathway under hypoxia condition. Schematic diagram showing that the PSF-Hakai-HIF-1 alpha signaling pathway. Under hypoxia condition, PSF-Hakai complex regulate HIF-1 alpha signaling, thus inhibiting downstream target gene VEGF, cell metabolism and angiogenesis eventually.

Automated summary

This study demonstrates that PSF inhibits HIF-1 alpha by recruiting Hakai, modulates mitochondrial bioenergetics and metabolism, and downregulates VEGF expression under hypoxic conditions, playing a crucial role in inhibiting pathological neovascularization associated with ophthalmopathy.