STAT3-mediated MMP-2 expression is required for 15-HETE-induced vascular adventitial fibroblast migration

• 15-HETE modulates pulmonary adventitial fibroblasts activity.
• The mechanism relies on JNK-STAT3 signaling pathway.
• MMP-2 may contribute to cell dynamic changes.
• Our study illustrates the mechanism behind a relevant player in hypertension.

ObjectiveVascular adventitial fibroblasts (VAFs) migration was involved in neointima formation, and increased 15-HETE levels contributed to vascular remodeling. However, how 15-HETE-induced VAF migration was not clear.Methods and results15-HETE-stimulated VAF phenotypic changes and migration as measured by the wound healing assay required STAT3 phosphorylation. JNK1 and CREB inhibition blocked 15-HETE-induced STAT3 activation and VAF changes. 15-HETE-induced MMP-2 expression and secretion were analyzed by Western blot and ELISA, respectively. MMP-2 knockdown blocked VAF migration and phenotypic alterations. JNK1, STAT3 and CREB blockade suppressed 15-HETE-induced MMP-2 expression in VAFs. MMP-2 promoter activity was assessed by chromatin immunoprecipitation using anti-STAT3 antibodies, which demonstrated that STAT3 was essential for 15-HETE-induced MMP-2 expression. Rats that suffered from hypoxia injury with or without treatment were examined. Pulmonary artery remodeling was obviously observed, and even the media was broken. MMP-2-positive staining was observed in the adventitia and intima. MMP-2 Serum secretion was enhanced as detected by ELISA, and MMP-2 and α-SMA protein expressions were increased after inducing hypoxia in the rats, which was restored in rats that had been administrated with NDGA.ConclusionThese results reveal that STAT3-mediated MMP-2 expression is required for 15-HETE induced-VAF migration.