Objectives: Coagulation factor XI (FXI) was reported to contribute to atherogenesis. The underlying mechanism remains unknown. We investigated the cellular effect of FXI and its mechanism in vascular smooth muscle cells.
Methods and main results: Activated FXI (FXIa) induced intracellular Ca²⁺ signaling mainly due to Ca²⁺ influx in the fura-2-loaded A7r5 cells, rat embryonic aorta smooth muscle cells. Pharmacological inhibitor (diltiazem) and genetic knockdown of L-type Ca²⁺ channel abolished the FXIa-induced Ca²⁺ influx. FXIa-induced Ca²⁺ signaling was abolished by atopaxar, a PAR₁ antagonist. FXIa, when pre-incubated with a proteinase inhibitor p-APMSF, failed to elicit Ca²⁺ signaling in A7r5 cells. FXIa failed to induce Ca²⁺ signal in embryonic fibroblasts derived from PAR₁-knockout mice. In vitro digestion assay revealed that FXIa cleaved the extracellular domain of PAR₁ at the same site that thrombin cleaved. FXIa accelerated cell migration of A7r5 cells in a wound healing assay. The acceleration of cell migration was partly inhibited by atopaxar and diltiazem.
Conclusions: We provides the first evidence that FXIa exerts cellular effect via PAR₁ in vascular smooth muscle cells.