Mechanisms regulating heterogeneity of hemostatic gene expression in endothelial cells

The hemostatic system involves an array of circulating coagulation factors that work in concert with platelets and the vascular endothelium to promote clotting in a space- and time-defined manner. Despite equal systemic exposure to circulating factors, bleeding and thrombotic diseases tend to prefer specific sites, suggesting an important role for local factors. This may be provided by endothelial heterogeneity. Endothelial cells differ not only between arteries, veins, and capillaries but also between microvascular beds from different organs, which present unique organotypic morphology and functional and molecular profiles. Accordingly, regulators of hemostasis are not uniformly distributed in the vasculature. The establishment and maintenance of endothelial diversity are orchestrated at the transcriptional level. Recent transcriptomic and epigenomic studies have provided a global picture of endothelial cell heterogeneity. In this review, we discuss the organotypic differences in the hemostatic profile of endothelial cells; we focus on 2 major endothelial regulators of hemostasis, namely von Willebrand factor and thrombomodulin, to provide examples of transcriptional mechanisms that control heterogeneity; finally, we consider some of the methodological challenges and opportunities for future studies.