The Regulatory Role of Coagulation Factors on Arterial Function

Abstract

The coagulation takes place in the physiological system of hemostasis. Hemostasis is known to be disturbed in many diseases leading to hemorrhages or thrombosis. Despite the role of coagulation in hemostasis, recent evidence suggest that coagulation factors are involved in other physiological as well as pathological processes related to vascular function such as blood pressure regulation, arterial stiffness or atherosclerosis. Many direct (through protease activated receptors; PARs) or indirect effects of several coagulation factors are now well described.

We are studying the interplay between the vascular phenotype at a physiological and a cellular level with coagulation factors. Previous work in the laboratory showed that coagulation factors such as tissue factor pathway inhibitor (TFPI) are related to modulations of arterial function. TFPI expression by vascular smooth muscle cells (VSCMs), is modulated by cyclic stretch. A 10% mechanic stretch at 1 Hz leads to increased synthesis of TFPI. This relation between TFPI and increased pulse pressure and aortic stiffness was present in a cohort of postmenopausal woman. The importance of elevated blood pressure was also studied in spontaneously hypertensive rats (SHR). In these rats thrombus formation was accelerated in carotid artery and could be reversed by an inhibitor the thrombin receptor PAR-1. Thrombus formation was accelerated due to the ability of VSMCs to support greater thrombin generation with an increased exposure of negatively charged phospholipids (1). Similarly, in obese Zucker rats mimicking the metabolic syndrome thrombin generation was increase at the surface of VSCMs. Circulating fibrinogen was increase in the Zucker rats and is also a marker of inflammation and vascular inflammation was increase in these rats. Indeed gelatinase activity which represent metalloproteinase-2 (MMP-2) and MMP-9 was elevated in the aortic wall. We found in this work that the prothrombotic phenotype of the blood compartment was reinforced by procoagulant properties of dedifferentiated and inflammatory VSMCs (2). Thrombin is the pivotal protease of coagulation and coagulation factor XI (FXI) is important for its amplification. In hypertension the thrombin driven FXI feedback activation was found to mediates the vascular inflammation and dysfunction. We found that FXI receptor glycoprotein Ibalpha on platelet support the increased thrombin generation increasing both platelets and leukocytes activation. This localised thrombin generated because of FXI triggers endothelial dysfunction and monocytes infiltration which are known to participates in the development of arterial hypertension. Moreover inhibition of FXI in angiotensin II infused mice and rats limit blood pressure increase and adverse effect of hypertension (3).

Coagulation factors are not only important for hemostasis. Studying their role in vascular function regulation is novel and important function now starts to be revealed. A number of important questions remains, concerning the ability of many cell types to synthetize coagulation factors that could have localized cellular effects in vascular or circulating immune cells. More work is also necessary to understand how circulating coagulation factors could move from the blood to the vascular wall (and inversely) and how this movement is modulated under pathological conditions as well as how cellular effects of coagulation factors could play a role in the vascular regulation of these pathologies.