Abstract
Tissue plasminogen activator (t-PA), the primary PA in vasculature, is synthesized and secreted from vascular endothelial cells (VECs). Besides other serine proteases involved in both coagulation and fibrinolysis, t-PA has unique characteristics of possessing physiological activity as a single chain form and being secreted as an active form. In blood there also exist plasminogen activator inhibitor type 1 (PAI-1), a member of serine protease inhibitor superfamily (SERPINS), which inhibits the activity of both single chain- and two chain- forms of t-PA by forming an equimolar high molecular weight complex. We have reported that total fibrinolytic activity in plasma is regulated by the balance between these two molecules, showing that increase in PAI-1 level under either physiological or pathological conditions suppresses fibrinolytic activity, whereas the enhanced t-PA secretion accelerates fibrinolysis. Recently, we have studied the dynamics of t-PA secretion from its containing granules in VECs using total internal reflection fluorescence microscopy (TIRFM). We obtained results suggesting that secreted t-PA by regulatory exocytosis stays on the membrane of VECs for certain period of time, and expresses its specific activity on VECs. PAI-1 appeared to modify the dynamics of t-PA secretion, and thus fibrinolytic activity on VECs.Showing these resuls, we discuss how fibrinolytic activity is regulated by t-PA and PAI-1 both in plasma and on VECs. We also want to discuss the physiological relevance of this regulatory mechanism which is naturally modified by many physiological stimuli [J Physiol Sci. 2006;56 Suppl:S49]
