Objective      To determine the effects of lipoxin A

4

(LXA

4

) on the expression of vas

cular endothelial growth factor (VEGF) in vivo and in vitro and investigate the possible underlying mechanism.       Methods       A total of 32 male SD rats (6 to 8 weeks old

weighing 200 to 250 g) were randomly and equally divided into 4 groups

that is

the normal control

BML-111 treatment group (LXA

4

receptor agonist)

adjuvant arthritis model group (AA)

and model plus BML-111 intervention group (AA＋BML-111). The AA model was induced by intradermal injection of complete Freund’s adjuvant into the left hind footpad of the rats. In the AA＋BML-111 group

the rats were supplemented with BML-111 daily for 28 d. Then the  synovium   from injured joints were harvested

the level of VEGF in the homogenates was determined by ELISA

and the total level and phosphorylated level of VEGF receptor 2 were determined by Western blot analysis. The rat fibroblast-like synoviocyte (FLS) RSC-364 was cultured in vitro and stimulated with interleukin-1β (IL-1β) in the absence or presence of LXA

4

(1 to 100 nmol/L) for 24 h. The concentrations of VEGF in the supernatant were determined by ELISA

the total levels and phosphorylated levels of p38

JNK and ERK

and the protein level of hypoxia-inducible factors 1α (HIF-1α) were determined by Western blotting.       Results      In the  synovium   from AA rats

LXA

4

down-regulated the generation of VEGF. It did not alter the total level of VEGFR2 but significantly suppressed the phosphorylation of VEGFR2. LXA

4

suppressed IL-1β-induced production of VEGF in FLS in a dose-dependent manner

reduced the levels of phosphorylated P38

JNK and ERK

and decreased the protein content of HIF-1α.       Conclusion       LXA

4

might down-regulate IL-1β-induced VEGF expression in RSC-364 cells via suppression of MAPK and HIF-1

which might regulate the angiogenesis and the formation of pannus during the progression of AA in rats

which may be a novel underlying mechanism of protective effects of LXA

4

on arthritis.