| First Author | Liu W | Year | 2019 |
| Journal | Am J Physiol Cell Physiol | Volume | 316 |
| Issue | 3 | Pages | C377-C392 |
| PubMed ID | 30566391 | Mgi Jnum | J:273344 |
| Mgi Id | MGI:6281066 | Doi | 10.1152/ajpcell.00426.2018 |
| Citation | Liu W, et al. (2019) Coagulation factor XI induces Ca(2+) response and accelerates cell migration in vascular smooth muscle cells via proteinase-activated receptor 1. Am J Physiol Cell Physiol 316(3):C377-C392 |
| abstractText | Activated coagulation factor XI (FXIa) is a serine proteinase that plays a key role in the intrinsic coagulation pathway. The analysis of FXI-knockout mice has indicated the contribution of FXI to the pathogenesis of atherosclerosis. However, the underlying mechanism remains unknown. We hypothesized that FXIa exerts vascular smooth muscle effects via proteinase-activated receptor 1 (PAR1). Fura-2 fluorometry revealed that FXIa elicited intracellular Ca(2+) signal in rat embryo aorta smooth muscle A7r5 cells. The influx of extracellular Ca(2+) played a greater role in generating Ca(2+) signal than the Ca(2+) release from intracellular stores. The FXIa-induced Ca(2+) signal was abolished by the pretreatment with atopaxar, an antagonist of PAR1, or 4-amidinophenylmethanesulfonyl fluoride (p-APMSF), an inhibitor of proteinase, while it was also lost in embryonic fibroblasts derived from PAR1(-/-) mice. FXIa cleaved the recombinant protein containing the extracellular region of PAR1 at the same site (R45/S46) as that of thrombin, a canonical PAR1 agonist. The FXIa-induced Ca(2+) influx was inhibited by diltiazem, an L-type Ca(2+) channel blocker, and by siRNA targeted to CaV1.2. The FXIa-induced Ca(2+) influx was also inhibited by GF109203X and rottlerin, inhibitors of protein kinase C. In a wound healing assay, FXIa increased the rate of cell migration by 2.46-fold of control, which was partly inhibited by atopaxar or diltiazem. In conclusion, FXIa mainly elicits the Ca(2+) signal via the PAR1/CaV1.2-mediated Ca(2+) influx and accelerates the migration in vascular smooth muscle cells. The present study provides the first evidence that FXIa exerts a direct cellular effect on vascular smooth muscle. |
