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.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Dai B, Zhu F, Chen Y, Zhou R, Wang Z, Xie Y, et al. ASIC1a promotes acid-induced autophagy in rat articular chondrocytes through the AMPK/FoxO3a pathway. Int J Mol Sci. 2017;18:E2125.
Chen Y, Zhu CJ, Zhu F, Dai BB, Song SJ, Wang ZQ, et al. Necrostatin-1 ameliorates adjuvant arthritis rat articular chondrocyte injury via inhibiting ASIC1a-mediated necroptosis. Biochem Biophys Res Commun. 2018;504:843–50.
Smeets TJ, Kraan MC, Galjaard S, Youssef PP, Smith MD, Tak PP. Analysis of the cell infiltrate and expression of matrix metalloproteinases and granzyme B in paired synovial biopsy specimens from the cartilage-pannus junction in patients with RA. Ann Rheum Dis. 2001;60:561–5.
Huh YH, Lee G, Lee KB, Koh JT, Chun JS, Ryu JH. HIF-2alpha-induced chemokines stimulate motility of fibroblast-like synoviocytes and chondrocytes into the cartilage-pannus interface in experimental rheumatoid arthritis mouse models. Arthritis Res Ther. 2015;17:302.
Yue L, Shen YX, Feng LJ, Chen FH, Yao HW, Liu LH, et al. Blockage of the formation of new blood vessels by recombinant human endostatin contributes to the regression of rat adjuvant arthritis. Eur J Pharmacol. 2007;567:166–70.
Hu W, Xia LJ, Chen FH, Wu FR, Tang J, Chen CZ, et al. Recombinant human endostatin inhibits adjuvant arthritis by down-regulating VEGF expression and suppression of TNF-alpha, IL-1beta production. Inflamm Res. 2012;61:827–35.
Rong C, Chen FH, Jiang S, Hu W, Wu FR, Chen TY, et al. Inhibition of acid-sensing ion channels by amiloride protects rat articular chondrocytes from acid-induced apoptosis via a mitochondrial-mediated pathway. Cell Biol Int. 2012;36:635–41.
Li X, Wu FR, Xu RS, Hu W, Jiang DL, Ji C, et al. Acid-sensing ion channel 1a-mediated calcium influx regulates apoptosis of endplate chondrocytes in intervertebral discs. Expert Opin Ther Targets. 2014;18:1–14.
Zhou RP, Dai BB, Xie YY, Wu XS, Wang ZS, Li Y, et al. Interleukin-1beta and tumor necrosis factor-alpha augment acidosis-induced rat articular chondrocyte apoptosis via nuclear factor-kappaB-dependent upregulation of ASIC1a channel. Biochim Biophys Acta Mol Basis Dis. 2018;1864:162–77.
Zhou RP, Wu XS, Wang ZS, Xie YY, Ge JF, Chen FH. Novel insights into acid-sensing ion channels: implications for degenerative diseases. Aging Dis. 2016;7:491–501.
Jing Z, Xu H, Chen X, Zhong Q, Huang J, Zhang Y, et al. The proton-sensing G-protein coupled receptor GPR4 promotes angiogenesis in head and neck cancer. PLoS ONE. 2016;11:e0152789.
Dewhirst MW, Richardson R, Cardenas-Navia I, Cao Y. The relationship between the tumor physiologic microenvironment and angiogenesis. Hematol Oncol Clin North Am. 2004;18:973–90.
Leske DA, Wu J, Mookadam M, Chen Y, Fautsch MP, Holmes JM, et al. The relationship of retinal VEGF and retinal IGF-1 mRNA with neovascularization in an acidosis-induced model of retinopathy of prematurity. Curr Eye Res. 2006;31:163–9.
Shi Q, Le X, Wang B, Abbruzzese JL, Xiong Q, He Y, et al. Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene. 2001;20:3751–6.
Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res. 2001;61:6020–4.
Dusenkova S, Ru F, Surdenikova L, Nassenstein C, Hatok J, Dusenka R, et al. The expression profile of acid-sensing ion channel (ASIC) subunits ASIC1a, ASIC1b, ASIC2a, ASIC2b, and ASIC3 in the esophageal vagal afferent nerve subtypes. Am J Physiol Gastrointest Liver Physiol. 2014;307:G922–30.
Grunder S, Chen X. Structure, function, and pharmacology of acid-sensing ion channels (ASICs): focus on ASIC1a. Int J Physiol Pathophysiol Pharmacol. 2010;2:73–94.
van Bemmelen MX, Huser D, Gautschi I, Schild L. The human acid-sensing ion channel ASIC1a: evidence for a homotetrameric assembly state at the cell surface. PLoS ONE. 2015;10:e0135191.
Wu X, Ren G, Zhou R, Ge J, Chen FH. The role of Ca(2+) in acid-sensing ion channel 1a-mediated chondrocyte pyroptosis in rat adjuvant arthritis. Lab Invest. 2019;99:499–513.
Zhou R, Wu X, Wang Z, Ge J, Chen F. Interleukin-6 enhances acid-induced apoptosis via upregulating acid-sensing ion channel 1a expression and function in rat articular chondrocytes. Int Immunopharmacol. 2015;29:748–60.
Sugimura N, Ikeuchi M, Izumi M, Kawano T, Aso K, Kato T, et al. Repeated intra-articular injections of acidic saline produce long-lasting joint pain and widespread hyperalgesia. Eur J Pain. 2015;19:629–38.
Zhang Y, Zhang T, Wu C, Xia Q, Xu D. ASIC1a mediates the drug resistance of human hepatocellular carcinoma via the Ca(2+)/PI3-kinase/AKT signaling pathway. Lab Invest. 2017;97:53–69.
Jernigan NL, Herbert LM, Walker BR, Resta TC. Chronic hypoxia upregulates pulmonary arterial ASIC1: a novel mechanism of enhanced store-operated Ca2+ entry and receptor-dependent vasoconstriction. Am J Physiol Cell Physiol. 2012;302:C931–40.
Duan B, Wang YZ, Yang T, Chu XP, Yu Y, Huang Y, et al. Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. J Neurosci. 2011;31:2101–12.
Choi YK, Kim JH, Lee DK, Lee KS, Won MH, Jeoung D, et al. Carbon monoxide potentiation of L-Type Ca(2+) channel activity increases HIF-1alpha-independent VEGF expression via an AMPKalpha/SIRT1-mediated PGC-1alpha/ERRalpha axis. Antioxid Redox Signal. 2017;27:21–36.
Riemann A, Reime S, Thews O. Tumor acidosis and hypoxia differently modulate the inflammatory program: measurements in vitro and in vivo. Neoplasia. 2017;19:1033–42.
Zhang HM, Liu MY, Lu JX, Zhu ML, Jin Q, Ping S, et al. Intracellular acidosis via activation of Akt-girdin signaling promotes post ischemic angiogenesis during hyperglycemia. Int J Cardiol. 2019;277:205–11.
Xie YY, Li Y, Zhou RP, Dai BB, Qian YJ, Wu XS, et al. Effects of autophagy on acid-sensing ion channel 1a-mediated apoptosis in rat articular chondrocytes. Mol Cell Biochem. 2018;443:181–91.
Zhou R, Zhu F, Wu X, Song S, Chen Y, Zhu C, et al. Effects of autophagy on apoptosis of articular chondrocytes in adjuvant arthritis rats. J Cell Mol Med. 2019;23:7879–84.
Wang YZ, Wang JJ, Huang Y, Liu F, Zeng WZ, Li Y, et al. Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction. Elife. 2015;4:e05682.
Chen X, Sun X, Wang Z, Zhou X, Xu L, Li F, et al. Involvement of acid-sensing ion channel 1a in gastric carcinoma cell migration and invasion. Acta Biochim Biophys Sin. 2018;50:440–6.
Thews O, Riemann A. Tumor pH and metastasis: a malignant process beyond hypoxia. Cancer Metastasis Rev. 2019;38:113–29.
Ibrahim-Hashim A, Estrella V. Acidosis and cancer: from mechanism to neutralization. Cancer Metastasis Rev. 2019;38:149–55.
Gregory NS, Brito RG, Fusaro M, Sluka KA. ASIC3 is required for development of fatigue-induced hyperalgesia. Mol Neurobiol. 2016;53:1020–30.
Ikeuchi M, Kolker SJ, Sluka KA. Acid-sensing ion channel 3 expression in mouse knee joint afferents and effects of carrageenan-induced arthritis. J Pain. 2009;10:336–42.
Krishtal O. The ASICs: signaling molecules? Modulators? Trends Neurosci. 2003;26:477–83.
Xiong ZG, Pignataro G, Li M, Chang SY, Simon RP. Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr Opin Pharmacol. 2008;8:25–32.
Cai F, Hong X, Tang X, Liu NC, Wang F, Zhu L, et al. ASIC1a activation induces calcium-dependent apoptosis of BMSCs under conditions that mimic the acidic microenvironment of the degenerated intervertebral disc. Biosci Rep. 2019;39:BSR20192708.
Zhou RP, Leng TD, Yang T, Chen FH, Xiong ZG. Acute ethanol exposure promotes autophagy-lysosome pathway-dependent ASIC1a protein degradation and protects against acidosis-induced neurotoxicity. Mol Neurobiol. 2019;56:3326–40.
Zhou R, Leng T, Yang T, Chen F, Hu W, Xiong ZG. Beta-estradiol protects against acidosis-mediated and ischemic neuronal injury by promoting ASIC1a (acid-sensing ion channel 1a) protein degradation. Stroke. 2019;50:2902–11.
de Weille J, Bassilana F. Dependence of the acid-sensitive ion channel, ASIC1a, on extracellular Ca(2+) ions. Brain Res. 2001;900:277–81.
Mari Y, Katnik C, Cuevas J. ASIC1a channels are activated by endogenous protons during ischemia and contribute to synergistic potentiation of intracellular Ca(2+) overload during ischemia and acidosis. Cell Calcium. 2010;48:70–82.
Zhang YH, Qian XW, Yang XJ, Niu RW, Song SJ, Zhu F, et al. ASIC1a induces synovial inflammation via the Ca2+/NFATc3/RANTES pathway. Theranostics. 2020;10:247–64.
Zeini M, Hang CT, Lehrer-Graiwer J, Dao T, Zhou B, Chang CP. Spatial and temporal regulation of coronary vessel formation by calcineurin-NFAT signaling. Development. 2009;136:3335–45.
Muller MR, Sasaki Y, Stevanovic I, Lamperti ED, Ghosh S, Sharma S, et al. Requirement for balanced Ca/NFAT signaling in hematopoietic and embryonic development. Proc Natl Acad Sci USA. 2009;106:7034–9.
Hilmi C, Guyot M, Pages G. VEGF spliced variants: possible role of anti-angiogenesis therapy. J Nucleic Acids. 2012;2012:162692.
Briancon-Marjollet A, Pepin JL, Weiss JW, Levy P, Tamisier R. Intermittent hypoxia upregulates serum VEGF. Sleep Med. 2014;15:1425–6.
Herbert LM, Resta TC, Jernigan NL. RhoA increases ASIC1a plasma membrane localization and calcium influx in pulmonary arterial smooth muscle cells following chronic hypoxia. Am J Physiol Cell Physiol. 2018;314:C166–76.
Li MH, Leng TD, Feng XC, Yang T, Simon RP, Xiong ZG. Modulation of acid-sensing ion channel 1a by Intracellular pH and its role in ischemic stroke. J Biol Chem. 2016;291:18370–83.
This work was supported by the National Science Foundation of China (Grant Number 81873986).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
Factors and Molecular Mechanisms Influencing the Protein Synthesis, Degradation and Membrane Trafficking of ASIC1a
Frontiers in Cell and Developmental Biology (2020)