ENDOTHELIAL CELL CONTROL OF PLATELET ACTIVATION: REGULATION OF SYNTHESIS AND SECRETION OF PROSTACYCLIN, NITRIC OXIDE AND VON WILLEBRAND FACTOR

摘要

Following vessel damage, endothelial cell properties are rapidly modulated to ensure that platelet activation and haemostatic plug formation occur efficiently at the site of the injury but do not lead to intravascular thrombosis. The main endoflielium-derived mediators are von Willebrand Factor (vWF), prostacydin (PGI_2) and nitric oxide (NO). Early studies demonstrated the importance of raised cytosolic Ca~(2+), [Ca~(2+)]_i, in the signal transduction pathways leading to secretion of vWF, PGI_2 and NO in response to agonists such as thrombin. More recently, it has been shown that NO synthesis can occur due to influx of external Ca~(2+) in the absence of detectable elevations of [Ca~(2+)]_i. We have now shown that rapid activation of the p42 MAP kinase pathway occurs when endothelial cells are stimulated by thrombin or histamine, and that this pathway in conjunction with raised [Ca~(2+)]_i is needed for PGI_2 synthesis, but not for NO synthesis. In contrast, sustained NO production in response to physical forces can be maintained in the absence of extracellular Ca~(2+) and apparently involves tyrosine phosphorylation signalling events in a manner that is not yet fully understood. Although thrombin and histamine are effective vWF secretagogues, other Ca~(2+)-mobilising agonists are not, indicating the existence of other as yet undefined signalling pathways, and recent reports suggest these can include activation of adenylyl cyclase. Thus despite substantial recent progress, the picture of receptor-linked and mechanically transduced mediator secretion by endothelial cells is not complete.