|| Checking for direct PDF access through Ovid
Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study evaluated the mechanisms underlying PAR1- and PAR2-induced activation of rat aortic adventitial fibroblasts, and whether PAR1 and PAR2 play a role in Ang II-induced AF activation and contribute to adventitial remodeling.In vitro experiment, AFs were cultured by tissue explant. AF proliferation was detected by CCK8 assay, AF migration by wound scratch assay, protein expression by Western blot, mRNA levels by real-time PCR. In vivo experiment, protein expression in the vascular adventitia was analyzed by immunofluorescence.We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-β and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins.In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes.