Extracellular tri- and diphosphate nucleosides are released into tissue fluids and plasma as a consequence of cellular responses to various pro- inflammatory stimuli, tissue damage and cell death. Extracellular nucleotides exert their effects on various cells through purinergic P2 type receptors and can cause cell activation and apoptosis. Our data show that extracellular ATP induces endothelial cell (EC) activation and phosphorylation of several proteins in EC, including focal adhesion kinase (FAK), paxillin, related adhesion focal tyrosine kinase (RAFTK), p130/cas, caveolin-1,Shc, and p38, SAPK/JNK and ERK MAP kinases. These proteins belong to various signal transduction pathways associated with cell cytoskeleton rearrangements, cell spreading, motility, cell proliferation, and apoptosis. We also found that extracellular nucleotides activate nuclear factor kappa B (NF-kappaB) and up-regulated expression of E-selectin, involved in the initial interaction of leukocytes with EC, leading to their transmigration into spots of inflammation. We intend to identify the receptor(s) responsible for up-regulation of the E- selectin and elucidate the mechanism of ATP-induced signal transduction leading to induction of E-selectin gene. Obtained results will help to elucidate the mechanisms of disease states that involve purinergic receptor signaling (e.g, inflammation, angiogenesis, atherogenesis, graft rejection). New findings about the mechanism of E- selectin regulation, including data revealing the origin of the activation of p38 MAPK and NF-kappaB by P2 receptors, will define the role of extracellular nucleotides in inflammation and other diseases. Completed studies should offer novel approaches how to control P2 receptors functions that can be useful in the treatment of vascular inflammation, thrombosis, cystic fibrosis and cancer through anti-angiogenic therapies.
