Succinate induces synovial angiogenesis in rheumatoid arthritis through metabolic remodeling and HIF-1α/VEGF axis

Background and purpose: In response to hypoxic succinate accumulates in arthritis synovium, however, the implication is little known. This study aims to investigate whether succinate could act as a metabolic signal linking metabolic alternation with angiogenesis in arthritis synovium. Experimental approach: The interaction between elevated succinate and VEGF production was examined in endothelial cells. Succinate production, HIF-1 alpha induction and angiogenesis in the hypoxic synovium of collagen-induced arthritis rats were also investigated. Key results: Intracellular succinate promoted VEGF production and induced angiogenic response dependent on HIF-1 alpha induction in endothelial cells. Luciferase reporter assay showed that succinate increased VEGF expression through gene promoter activation dependent on HIF-1 alpha induction. Intracellular succinate released into intercellular space, where extracellular succinate activated succinate receptor G-protein-coupled receptor 91 (GPR91) and induced VEGF production, further exacerbating angiogenesis. In addition, TGF-beta 1 treatment increased succinate production due to the reversal of succinate dehydrogenase (SDH) activation, and consistently, SDH inhibitor dimethyl malonate reduced angiogenesis in the arthritis synovium. Conclusion and implications: More than an intermediate, succinate functioned as a signaling molecule to link metabolic reprograming with angiogenesis. Intracellular succinate induced angiogenesis through HIF-1 alpha induction, while extracellular succinate acted on GPR91 activation, working together to disturb energy metabolism and exacerbate inflammation and angiogenesis in arthritis synovium. Our work suggested that suppression of SDH could prevent succinate accumulation and inhibit angiogenesis via blocking HIF-1 alpha/VEGF axis. This finding not only provides a novel insight into angiogenesis, but also reveals a potential therapeutical strategy to attenuate revascularization in arthritis.