Charlotte Kawecki1, Nathalie Hézard1, Olivier Bocquet1, Gaël Poitevin1, Fanja Rabenoelina1, Alexandre Kauskot1, Laurent Duca1, Sébastien Blaise1, Béatrice Romier1, Laurent Martiny1, Philippe Nguyen1, Laurent Debelle1, Pascal Maurice2. 1. From the URCA, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Reims, France (C.K., O.B., F.R., L. Ducca, S.B., B.R., L.M., L. Debelle, P.M.); EA3801, Hémostase et remodelage vasculaire post-ischémique (HERVI), UFR de Médecine, Reims, France (N.H., G.P., P.N.); CHU Reims, Hôpital Robert Debré, Laboratoire d'Hématologie, Reims, France (N.H., P.N.); INSERM UMRS 1140, Université Paris Descartes, Sorbonne Paris Cité, France (A.K.); and INSERM U770, Le Kremlin Bicêtre, Université Paris-Sud, Le Kremlin Bicêtre, France (A.K.). 2. From the URCA, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Reims, France (C.K., O.B., F.R., L. Ducca, S.B., B.R., L.M., L. Debelle, P.M.); EA3801, Hémostase et remodelage vasculaire post-ischémique (HERVI), UFR de Médecine, Reims, France (N.H., G.P., P.N.); CHU Reims, Hôpital Robert Debré, Laboratoire d'Hématologie, Reims, France (N.H., P.N.); INSERM UMRS 1140, Université Paris Descartes, Sorbonne Paris Cité, France (A.K.); and INSERM U770, Le Kremlin Bicêtre, Université Paris-Sud, Le Kremlin Bicêtre, France (A.K.). pascal.maurice@univ-reims.fr.
Abstract
OBJECTIVE: Elastin is the major structural extracellular matrix component of the arterial wall that provides the elastic recoil properties and resilience essential for proper vascular function. Elastin-derived peptides (EDP) originating from elastin fragmentation during vascular remodeling have been shown to play an important role in cell physiology and development of cardiovascular diseases. However, their involvement in thrombosis has been unexplored to date. In this study, we investigated the effects of EDP on (1) platelet aggregation and related signaling and (2) thrombus formation. We also characterized the mechanism by which EDP regulate thrombosis. APPROACH AND RESULTS: We show that EDP, derived from organo-alkaline hydrolysate of bovine insoluble elastin (kappa-elastin), decrease human platelet aggregation in whole blood induced by weak and strong agonists, such as ADP, epinephrine, arachidonic acid, collagen, TRAP, and U46619. In a mouse whole blood perfusion assay over a collagen matrix, kappa-elastin and VGVAPG, the canonical peptide recognizing the elastin receptor complex, significantly decrease thrombus formation under arterial shear conditions. We confirmed these results in vivo by demonstrating that both kappa-elastin and VGVAPG significantly prolonged the time for complete arteriole occlusion in a mouse model of thrombosis and increased tail bleeding times. Finally, we demonstrate that the regulatory role of EDP on thrombosis relies on platelets that express a functional elastin receptor complex and on the ability of EDP to disrupt plasma von Willebrand factor interaction with collagen. CONCLUSIONS: These results highlight the complex nature of the mechanisms governing thrombus formation and reveal an unsuspected regulatory role for circulating EDP in thrombosis.
OBJECTIVE:Elastin is the major structural extracellular matrix component of the arterial wall that provides the elastic recoil properties and resilience essential for proper vascular function. Elastin-derived peptides (EDP) originating from elastin fragmentation during vascular remodeling have been shown to play an important role in cell physiology and development of cardiovascular diseases. However, their involvement in thrombosis has been unexplored to date. In this study, we investigated the effects of EDP on (1) platelet aggregation and related signaling and (2) thrombus formation. We also characterized the mechanism by which EDP regulate thrombosis. APPROACH AND RESULTS: We show that EDP, derived from organo-alkaline hydrolysate of bovine insoluble elastin (kappa-elastin), decrease humanplatelet aggregation in whole blood induced by weak and strong agonists, such as ADP, epinephrine, arachidonic acid, collagen, TRAP, and U46619. In a mouse whole blood perfusion assay over a collagen matrix, kappa-elastin and VGVAPG, the canonical peptide recognizing the elastin receptor complex, significantly decrease thrombus formation under arterial shear conditions. We confirmed these results in vivo by demonstrating that both kappa-elastin and VGVAPG significantly prolonged the time for complete arteriole occlusion in a mouse model of thrombosis and increased tail bleeding times. Finally, we demonstrate that the regulatory role of EDP on thrombosis relies on platelets that express a functional elastin receptor complex and on the ability of EDP to disrupt plasma von Willebrand factor interaction with collagen. CONCLUSIONS: These results highlight the complex nature of the mechanisms governing thrombus formation and reveal an unsuspected regulatory role for circulating EDP in thrombosis.