RA Fibroblast-Like Synoviocytes Derived Extracellular Vesicles Promote Angiogenesis by miRNA-1972 Targeting p53/mTOR Signaling in Vascular Endotheliocyte

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory in joints. Invasive pannus is a characteristic pathological feature of RA. RA fibroblast-like synoviocytes (FLSs) are showed tumor-like biological characters that facilitate pannus generation. Importantly, it has been documented that extracellular vesicle (EVs) derived microRNAs have a vital role of angiogenesis in various immune inflammatory diseases. However, whether RA FLSs derived EVs can facilitate angiogenesis and the underlying mechanism is undefined. Herein, we aim to investigate the key role of RA FLSs derived EVs on angiogenesis in endothelial cells (ECs). We indicate that RA FLSs derived EVs promote ECs angiogenesis by enhancing migration and tube formation of ECs in vitro. Also, we confirm that RA FLSs derived EVs can significantly facilitate ECs angiogenesis with a matrigel angiogenesis mice model. In terms of the mechanisms, both RNAs and proteins in EVs play roles in promoting ECs angiogenesis, but the RNA parts are more fundamental in this process. By combining microRNA sequencing and qPCR results, miR-1972 is identified to facilitate ECs angiogenesis. The blockage of miR-1972 significantly abrogated the angiogenesis stimulative ability of RA FLSs derived EVs in ECs, while the overexpression of miR-1972 reversed the effect in ECs. Specifically, the p53 level is decreased, and the phosphorylated mTOR is upregulated in miR-1972 overexpressed ECs, indicating that miR-1972 expedites angiogenesis through p53/mTOR pathway. Collectively, RA FLSs derived EVs can promote ECs angiogenesis via miR-1972 targeted p53/mTOR signaling, targeting on RA FLSs derived EVs or miR-1972 provides a promising strategy for the treatment of patients with RA.

The synovial fluid fibroblast-like synoviocyte: A long-neglected piece in the puzzle of rheumatoid arthritis pathogenesis

“…There is an increasing interest within the research community in analyzing tissue-resident FLS and their role in the development of RA. Recent data confirm the importance of these cells in synovial inflammation, joint destruction and even disease spread into distal sites (2,7,8).…”

“…SF is known to contain several immune cells and inflammatory cytokines, together entertaining inflammation in the affected area (5). RA pathology involves abnormalities of both the immune system (including T cells, B cells, plasma cells, dendritic cells, macrophages and mast cells) and fibroblast-like synoviocyte (FLS) activity (6,7).…”

Differential Expression of microRNAs in Serum of Patients with Chronic Painful Polyneuropathy and Healthy Age-Matched Controls

“…Confirming the potential targets and their effects/pathways found by our miRDB and the GO analysis, our literature research yielded the first hints of their involvement in hemorheological abnormalities such as hypertension/coronary artery calcification ( hsa -miR-3135b), pulmonary arterial hypertension ( hsa -miR-584-5p), angiogenesis/hypoxia ( hsa -miR-12136), and damaged vascular smooth muscles ( hsa -miR-550a-3p) [ 41 , 42 , 43 , 44 , 45 , 46 ]. Since the control group was lighter than the patient group (72.28 ± 8.83 kg vs. 85.51 ± 16.87 kg), the hsa -miR-584-5p and hsa -miR-550a-3p results may be due to this difference, as both miRNAs have also been linked to obesity/insulin resistance [ 47 , 48 ].…”

LncRNA HOTAIR regulates the PI3K/AKT pathway via the miR‐126‐3p/PIK3R2 axis to participate in synovial angiogenesis in rheumatoid arthritis

“…This exacerbates RA severity by contributing to synovial hyperplasia and inflammation. 8 Therefore, regulating angiogenesis induced by FLS is a potential strategy for the treatment of RA.…”

“…During RA activity, FLS produces a multitude of angiogenic factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which pathologically alter endothelial cell activity and promote joint angiogenesis. This exacerbates RA severity by contributing to synovial hyperplasia and inflammation 8 . Therefore, regulating angiogenesis induced by FLS is a potential strategy for the treatment of RA.…”