Endothelial cells play a critical role in the initiation of vascular inflammation and thrombosis. Stimulated by vascular injury or inflammatory agonists, endothelial cells express mediators that regulate leukocyte trafficking and platelet activation. The kinetics of endothelial activation include an early phase mediated by the rapid release of previously synthesized factors, and a later phase mediated by the synthesis of new proteins. The early inflammatory response of endothelial cells includes the exocytosis of Weibel-Palade bodies, endothelial granules that contain yon Willebrand Factor (vWF) and P-selectin. Exocytosis of Weibel-Palade bodies releases vWF which regulates platelet adhesion and aggregation, and translocates P-selectin to the endothelial surface where it regulates leukocyte rolling. Thus endothelial exocytosis plays an important role in mediating vascular inflammation and thrombosis. The regulation of endothelial exocytosis is partially understood. Exocytosis is a form of vesicle trafficking in which the granule fuses with the cellular plasma membrane, releasing its contents into the extracellular space and translocating transmembrane proteins to the surface of the cell. Several families of proteins regulate exocytosis, including N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein receptors (SNAREs), rab GTPases, and Munc. We recently showed that NSF plays a critical role in the regulation of exocytosis of Weibel-Palade bodies. We also discovered that nitric oxide (NO) inhibits exocytosis by targeting NSF. Our observations explain in part how NO inhibits vascular inflammation and thrombosis. The over-all goal of our studies is to explore the molecular mechanisms by which endothelial exocytosis regulates vascular inflammation. This application focuses on NSF regulation of endothelial cell exocytosis. We plan to continue our studies of how radicals regulates NSF. Next we plan to study how specific enzymes reduce oxidized NSF. Finally, we plan to develop a novel class of drugs that decrease vascular inflammation by targeting endothelial cell exocytosis.
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