title: Intracellular signaling controls endothelial cell prostacyclin secretion and regulation of blood clotting time.
abstract: Blood is constantly in contact with a biological material, the blood vessel wall, without the need for anticoagulants to prevent clot formation on the vessel wall; however, man-made biomaterials require anticoagulants to prevent clot formation on the biomaterial. This study seeks to understand how some biomaterials elicit anticoagulant responses from endothelial cells (ECs), whereas others do not. Partial least squares regression analysis was used to correlate the activity of four relevant signaling molecules [extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), Akt, and IκB kinase (IKK)] with human umbilical vein EC secretion of prostacyclin and clotting time of whole blood in contact with these cells. Prostacyclin secretion was increased when JNK activity (mean of all time-points) was elevated and IKK activity at 30 min was reduced. In addition, the clotting time, R-time measured by thromboelastography, was increased (reduced coagulability) when activity of both ERK and JNK (mean of all time-points) were increased and when Akt activity was increased at longer contact times (24-72 h after cell contact with material). Inhibition of each signaling molecule with subsequent testing for prostacyclin secretion and R-time confirmed the interrelationship between EC intracellular signaling and prostacyclin secretion. Generally, JNK inhibition decreased and IKK inhibition increased prostacyclin secretion. Inhibition of ERK or JNK generally increased coagulability, and Akt inhibition decreased the R-time of samples normally eliciting reduced coagulability. These findings increase our understanding of the signaling pathways involved in endothelial prostacyclin release and suggest targets for developing EC-seeded biomaterial surfaces that can minimize coagulation.
authors: School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona, USA.
authors: Venkat
authors: V
authors: Shankarraman
authors: Grace
authors: G
authors: Davis-Gorman
authors: Paul F
authors: PF
authors: McDonagh
authors: Michael R
authors: MR
authors: Caplan
mesh_terms: D000818:Animals; D011464:Epoprostenol / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D016018:Least-Squares Analysis; D008954:Models, Biological; D015398:Signal Transduction; D013916:Thrombelastography; D014914:Whole Blood Coagulation Time
chemical_list: D011464:Epoprostenol