title: Elastin-derived peptides are new regulators of thrombosis.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kawecki
authors.affiliation: 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.).
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hézard
authors.affiliation: 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.).
authors.forename: Olivier
authors.initials: O
authors.lastname: Bocquet
authors.affiliation: 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.).
authors.forename: Gaël
authors.initials: G
authors.lastname: Poitevin
authors.affiliation: 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.).
authors.forename: Fanja
authors.initials: F
authors.lastname: Rabenoelina
authors.affiliation: 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.).
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kauskot
authors.affiliation: 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.).
authors.forename: Laurent
authors.initials: L
authors.lastname: Duca
authors.affiliation: 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.).
authors.forename: Sébastien
authors.initials: S
authors.lastname: Blaise
authors.affiliation: 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.).
authors.forename: Béatrice
authors.initials: B
authors.lastname: Romier
authors.affiliation: 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.).
authors.forename: Laurent
authors.initials: L
authors.lastname: Martiny
authors.affiliation: 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.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: 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.).
authors.forename: Laurent
authors.initials: L
authors.lastname: Debelle
authors.affiliation: 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.
authors.forename: Pascal
authors.initials: P
authors.lastname: Maurice
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D043402:Cathepsin A / Q000097:blood; D002417:Cattle; D003094:Collagen / Q000097:blood; D004549:Elastin / Q000097:blood / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D051379:Mice; D009439:Neuraminidase / Q000097:blood; D009842:Oligopeptides / Q000097:blood / Q000737:chemistry / Q000502:physiology; D010446:Peptide Fragments / Q000097:blood / Q000737:chemistry / Q000502:physiology; D010974:Platelet Aggregation / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000097:blood; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood / Q000209:etiology*; D066253:Vascular Remodeling / Q000502:physiology; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011956:Receptors, Cell Surface; C054901:elastin-binding proteins; D014841:von Willebrand Factor; D003094:Collagen; D004549:Elastin; C042635:valyl-glycyl-valyl-alanyl-prolyl-glycine; D009439:Neuraminidase; D043402:Cathepsin A
keywords: extracellular matrix; platelet; thrombosis; vascular remodeling; von Willebrand Factor