Regulation of Endothelial Progenitor Cell Function by Plasma Kallikrein-Kinin System

Circulating endothelial progenitor cells (EPCs) are a hierarchy of pluripotent cells in peripheral blood capable of differentiating into mature endothelial cells destined for blood vessel formation[1]. These cells have the ability to be mobilized to the site of vascular injury or tissue ischemia, and they differentiate into mature endothelial cells. They are a major determinant of a postnatal mechanism for neovascularization and vascular remodeling, and play an important role in endothelial cell and vessel maintenance. However, in patients with atherosclerosis and cardiovascular disease, EPCs are reduced in number and impaired in function, which are negatively correlated with the atherosclerotic risk factors, and may contribute to vascular dysfunction[2]. For example, the frequency of circulating EPCs is reduced 50% in patients with coronary artery disease, and their EPCs display an impaired migratory response[3]. Moreover, although EPCs successfully restore endothelial function and enhance angiogenesis after tissue ischemia in animal models, the clinical administration of EPCs to patients has had limited efficacy. It is likely that EPCs are targets of endogenous angiogenic inhibitors elaborated in the setting of atherosclerosis. Therefore, understanding the factors and mechanisms that affect EPC function and number may not only provide new insights into the pathogenesis of vasculogenesis, but also promote development of specific therapies to ultimately correct EPC dysfunction and prevent progression of atherosclerosis. The plasma kallikrein–kinin system (KKS) consists of the proteins factor XII, prekallikrein, and high molecular weight kininogen (HK)[4-5]. This system widely participates in maintenance of the cardiovascular phenotype, and displays multiple physiologic and pathophysiological activities, such as blood pressure adjustment, modulation of thrombosis, regulation of endothelial cell function and angiogenesis. Plasma HK, which is synthesized and released from the liver, is a major component of the KKS and is responsible for the association of the KKS with cell surface. The plasma membrane of endothelial cells is an important site for the assembly and activation of the KKS. Activation of the KKS is triggered in vivo by tissue destruction or by thrombus development, and results in cleavage of HK by kallikrein and generation of two-chain HK (HKa) and a nonapeptide bradykinin[6]. HKa