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Acidosis induces synovial fibroblasts to release vascular endothelial growth factor via acid-sensitive ion channel 1a

Abstract

Acid-sensitive ion channel 1a (ASIC1a) is a member of the extracellular H+ activated cation channel family. Studies have shown that tissue acidification contributes to the formation of microvessels in rheumatoid arthritis (RA) synovial tissue, but its underlying mechanisms remain unclear. The purpose of this study was to investigate the role of tissue acidification in microvascular formation of arthritic synovial tissue and the effect of ASIC1a on vascular endothelial growth factor (VEGF) release from arthritic synovial tissue. Our results indicate that ASIC1a expression, VEGF expression, and microvessel density (MVD) are elevated in RA synovial tissue and adjuvant arthritis (AA) rat synovial tissue. When AA rats were treated with ASIC1a-specific blocker psalmotoxin-1 (PcTx-1), the expression of ASIC1a, VEGF expression, and MVD were all reduced. Acidification of RA synovial fibroblasts (RASF) can promote the release of VEGF. PcTx-1 and ASIC1a-short hairpin RNA can inhibit acid-induced release of VEGF. In addition, the ASIC1a overexpression vector can promote acid-induced VEGF release. This indicates that extracellular acidification induces the release of VEGF by RASF via ASIC1a. These findings suggest that blocking ASIC1a mediates the release of VEGF from synoviocytes may provide a potential therapeutic strategy for RA therapy.

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Fig. 1: ASIC1a is highly expressed in RA synovial tissue.
Fig. 2: ASIC1a regulates the release of VEGF by RASF.
Fig. 3: PcTx-1 can reduce joint damage and prevent arthritis in AA rats.
Fig. 4: PcTx-1 can reduce VEGF expression in the synovium of AA rats, prevent vascular remodeling and new blood vessel formation.
Fig. 5: Schematic diagram of RA synovial angiogenesis induced by acid.

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Acknowledgements

This work was supported by the National Science Foundation of China (Grant Number 81873986).

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Correspondence to Feihu Chen.

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Qian, X., Zhang, Y., Tao, J. et al. Acidosis induces synovial fibroblasts to release vascular endothelial growth factor via acid-sensitive ion channel 1a. Lab Invest 101, 280–291 (2021). https://doi.org/10.1038/s41374-020-0423-6

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