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Geniposide downregulates the <scp>VEGF</scp> / <scp>SphK1</scp> / <scp>S1P</scp> pathway and alleviates angiogenesis in rheumatoid arthritis in vivo and in vitro
- Source :
- Phytotherapy Research. 35:4347-4362
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- The VEGF/SphK1/S1P pathway is closely related to angiogenesis in rheumatoid arthritis (RA), but the precise underlying mechanisms are unclear at present. Here, we explored the involvement of the VEGF/SphK1/S1P cascade in RA models and determined the effects of GE intervention. Our results showed abnormal expression of proteins related to this pathway in RA synovial tissue. Treatment with GE effectively regulated the signal axis, inhibited angiogenesis, and alleviated RA symptoms. In vitro, TNF-ɑ enhanced the VEGF/SphK1/S1P pathway in a co-culture model of fibroblast-like synoviocytes (FLS) and vascular endothelial cells (VEC). GE induced downregulation of VEGF in FLS, restored the dynamic balance of pro-/antiangiogenic factors, and suppressed SphK1/S1P signaling in VEC, resulting in lower proliferation activity, migration ability, tube formation ability, and S1P secretion ability of VEC cells. Additionally, SphK1-specific small interfering RNA (siRNA) blocked the VEGF/SphK1/S1P cascade, which can effectively alleviate the stimulatory effect of FLS on VEC and further enhanced the therapeutic effect of GE. Taken together, our results demonstrate that GE suppresses the VEGF/SphK1/S1P pathway and alleviates the stimulation of VEC by FLS, thereby preventing angiogenesis and promoting therapeutic effects against RA.
- Subjects :
- Vascular Endothelial Growth Factor A
Small interfering RNA
Angiogenesis
Arthritis, Rheumatoid
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
In vivo
Humans
Iridoids
Secretion
Sphingosine-1-Phosphate Receptors
Cells, Cultured
Adaptor Proteins, Signal Transducing
Cell Proliferation
Pharmacology
Tube formation
0303 health sciences
Neovascularization, Pathologic
Chemistry
Synovial Membrane
030302 biochemistry & molecular biology
Endothelial Cells
Fibroblasts
In vitro
030220 oncology & carcinogenesis
Cancer research
Tumor necrosis factor alpha
Signal Transduction
Subjects
Details
- ISSN :
- 10991573 and 0951418X
- Volume :
- 35
- Database :
- OpenAIRE
- Journal :
- Phytotherapy Research
- Accession number :
- edsair.doi.dedup.....15b628f44775ff62ea4664be988df5fe