Regulation of gene expression in vascular cells by coagulation proteins.

Abstract

Receptors of vascular cells and coagulation proteins form a tightly integrated and balanced system, providing regulation to coagulation and mediating a response to coagulation by the vascular cells. Endothelial and smooth muscle cells express a variety of proteins directly participating in hemostasis. Engagement of activated coagulation proteins by their specific receptors on the vascular cell surface, in turn, activates these cells and leads to expression of genes involved in coagulation, angiogenesis, leukocyte adhesion, regulation of the vascular wall tone, etc. The signals inducing the expression of target genes are mediated by protease-activated receptors, which are shared among coagulation proteases. However, differences in mechanisms of activation of these receptors, as well as the presence of specific receptors for each coagulation protein and structures of promoters of target genes may provide specificity in the responses of vascular cell types to different coagulation factors. Activation of gene expression in vascular cells by coagulation proteases accounts for the long-term consequences of coagulation in disorders such as atherosclerotic lesion development, cancer growth, and inflammation. Multiple intracellular pathways and specific transcriptional mechanisms activated by coagulation proteins represent an attractive target for drug design, providing the possibility of controlling the adverse effects of coagulation activation without interfering with the hemostatic requirements of coagulation. This review discusses regulation of gene expression in vascular cells by thrombin, tissue factor, factor VIIa, factor Xa and protein C. Differences and similarities in mechanisms of receptor activation, the pathological profiles of genes activated by these coagulation factors, and recently described transcriptional mechanisms that they induce are discussed.