Membrane thrombomodulin levels are decreased during hypoxia and restored by cAMP and IBMX

Thrombomodulin is a membrane glycoprotein expressed by endothelium and is a receptor for thrombin. The thrombin-thrombomodulin complex inactivates the procoagulant activity of thrombin and catalyzes activation of protein C(1). The decrease in thrombomodulin expression at the surface of the vascular endothelium may contribute to the development of thrombosis. In vitro studies have shown that cytokines (TNF, IL-1) or endotoxins down regulate thrombomodulin expression (2, 3, 4) whereas histamine (5), retinoic acid (6) and cAMP analogs (7, 8) increase its expression. Hypoxia is frequently related to disorders of the vascular system such as atheromatous arterial disease and venous insufficiency (9). Clinically, hypoxia induces an increase in vascular permeability (10) and a prothrombotic tendency (12). In vitro, it has been demonstrated that hypoxia is able to modify endothelial properties. In effect, hypoxia has been shown to down regulate thrombornodulin expression on bovine arterial endothelial cells (BAEC) and microvascular endothelial cells (11, 13, 14). Moreover, it has been demonstrated that hypoxia decreases endothelial cell barrier function by lowering cAMP levels (15). cAMP is the major up regulator of thrombomodulin expression, so we investigated the effect of agents able to increase cAMP levels on membrane thrombomodulin expression in hypoxic conditions on HUVEC