Tissue Factor–Factor VIIa complex induces cytokine expression in coronary artery smooth muscle cells

ObjectiveWithin atherosclerotic lesions Tissue Factor (TF)–Factor VIIa (FVIIa) not only contributes to thrombotic events but also alters vascular remodeling through enhancement of migration. Moreover, the TF–FVIIa–FXa complex activates protease-activated receptors (PAR). TF/FVIIa/PAR-2 signaling has also been shown to promote proliferation and metastasis of tumor cells. Since coagulation factors promote inflammation which plays a major role during atherosclerosis as well as tumor metastasis this study sought to investigate the effects of FVIIa on the inflammatory response in vascular cells.Methods/resultsFVIIa induces interleukin-8 (IL-8) and IL-6 in primary smooth muscle cells (SMC), which was correlated to the expression of TF and PAR-2 as shown by immunoassay and qRT-PCR. The effect was dose-dependent and required TF, the proteolytic activity of FVIIa and PAR-2. Secondary effects of downstream coagulation factors were excluded. No proinflammatory FVIIa effect was observed in endothelial cells (EC) and mononuclear cells (MNC), expressing either TF or PAR-2. In atherosclerotic lesions mRNA expression of PAR-1, PAR-2 and IL-8 was elevated compared to healthy vessels indicating a role for PAR-1 and PAR-2 signaling in atherosclerosis.ConclusionIn addition to the procoagulant and promigratory role of the TF–FVIIa complex we identify a proinflammatory role of FVIIa in human SMC dependent on expression of TF and PAR-2 that provides yet another link between coagulation and inflammation.