The interplay between fibroblast‐like synovial and vascular endothelial cells leads to angiogenesis via the sphingosine‐1‐phosphate‐induced RhoA‐F‐Actin and Ras‐Erk1/2 pathways and the intervention of geniposide

Abstract

The changes of fibroblast‐like synoviocytes (FLSs) and vascular endothelial cells (VECs) biological functions are closely related to angiogenesis in rheumatoid arthritis (RA). Nevertheless, how the crosstalk between FLSs and VECs interferes with RA is far from being clarified. Herein, we studied the effect of the reciprocal interactions between FLSs and VECs on angiogenesis and mechanism of geniposide (GE). After administration of GE, improvement of synovial hyperplasia in adjuvant arthritis rats was accompanied by downregulation of SphK1 and p‐Erk1/2. The dynamic interaction between FLSs and VECs triggers the release of S1P by activating p‐Erk1/2 and SphK1, then activating RhoA‐F‐actin and Ras‐Erk1/2 pathways. When exposed to the inflammatory microenvironment mediated by FLSs‐VECs crosstalk, proliferation, migration, and permeability of VECs were enhanced, the angiogenic factors were imbalanced. Meanwhile, the proliferation and secretory ability of FLSs increased. Interestingly, depletion of S1P or blocking of the activation of SphK1 by GE and PF‐543 prevented the changes. In conclusion, S1P released during FLSs‐VECs crosstalk changed their biological functions by activating RhoA‐F‐actin and Ras‐Erk1/2 pathways. GE acted on p‐Erk1/2 and SphK1, inhibited the secretion of S1P, and blocked the interplay between FLSs and VECs. These results provide new insights into the mechanism of angiogenesis in RA.

The protective effect of natural medicines in rheumatoid arthritis via inhibit angiogenesis

“…These findings provided insight into the process of angiogenesis in the inhibition of geniposide. These data confirm that Geniposide is able to inhibit angiogenesis through several pathways and is expected to be developed as an angiogenesis inhibitor (Deng et al, 2021).…”

BNIP3 mediates the different adaptive responses of fibroblast-like synovial cells to hypoxia in patients with osteoarthritis and rheumatoid arthritis

“…The target protein was separated by 12% SDS–polyacrylamide gel. Western blot was performed as previously described (Deng et al 2021 ). The main antibodies used for immunoblotting are as follows: Bax (1:1000, Proteintech), Bcl-XL (1:1000, Proteintech), Beclin-1 (1:1000, Proteintech), light chain 3 (LC3, 1:1000, Proteintech), BNIP3 (1:1000, ZEN BIO), HIF-1α (1:1000, ZEN BIO), cyclin D1 (1:1000, ZEN BIO), PCNA (1:1000, ZEN BIO).…”

Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases

“…The dynamic balance between pro-/anti-angiogenic factors was disrupted in abnormally proliferating FLS and VECs, synovial microvascular neogenesis was induced by VEGF mediated SphK1/S1P/S1PR1. PF-543 exert an anti-angiogenic effect by inhibiting SphK1 ( Sun et al, 2020 ; Deng et al, 2021 ). The inflammatory microenvironment of synovium is produced by a large number of inflammatory cells infiltration, which is characterized by up-regulated cytokines, such as TNF-α, IL-1β and IL-6 ( Kuwabara et al, 2017 ).…”

“…A recent study has proved that PF-543 reduces apoptosis in the lungs of mice after acute ethanol intoxication, and inhibits neutrophil infiltration and the release of inflammatory cytokines to reduce lung injury ( Chen et al, 2021b ). As the most effective SphK1 inhibitor so far, PF-543 can inhibit inflammation in RA model ( Deng et al, 2021 ), ulcerative colitis model ( Liu and Jiang, 2020 ) and mouse pulmonary hypertension hypoxia model ( Ha et al, 2020 ) in vivo and in vitro , mainly by inhibiting the release of inflammatory cytokines and the change of cell biological function. In addition to inflammatory response, PF-543 plays a therapeutic role in angiogenesis in the pathogenesis of RA and microvascular leakage induced by sepsis ( Zhong et al, 2020 ).…”