title: Erythrocyte microparticles can induce kidney vaso-occlusions in a murine model of sickle cell disease.
abstract: Patients with sickle cell disease suffer from painful crises associated with disseminated vaso-occlusions, increased circulating erythrocyte microparticles (MPs), and thrombospondin-1 (TSP1). MPs are submicron membrane vesicles shed by compromised or activated cells. We hypothesized that TSP1 mediates MP shedding and participates in vaso-occlusions. We injected TSP1 to transgenic SAD mice with sickle cell disease and characterized circulating phosphatidylserine+ MPs by FACS. TSP1 stimulated MPs in plasma and initiated vaso-occlusions within minutes. In vitro, TSP1 triggered rapid erythrocyte conversion into spicule-covered echinocytes, followed by MP shedding. MP shedding was recapitulated by peptides derived from the TSP1 carboxyterminus. We purified MPs shed by erythrocytes in vitro and administered them back to SAD mice. MPs triggered immediate renal vaso-occlusions. In vitro, MPs triggered the production of radical oxygen species by endothelial monolayers, favored erythrocyte adhesion, and induced endothelial apoptosis. MPs also compromised vasodilation in perfused microvessels. These effects were inhibited by saturating MP phosphatidylserine with annexin-V, or with inhibitors of endothelial ROS production. We conclude that TSP1 triggers erythrocyte MP shedding. These MPs induce endothelial injury and facilitate acute vaso-occlusive events in transgenic SAD mice. This work supports a novel concept that toxic erythrocyte MPs may connect sickle cell anemia to vascular disease.
authors.affiliation: Paris Center for Cardiovascular Research, INSERM UMR s-970, Hôpital Européen Georges Pompidou, et Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Stéphane M
authors.initials: SM
authors.lastname: Camus
authors.forename: Blandine
authors.initials: B
authors.lastname: Gausserès
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonnin
authors.forename: Laurent
authors.initials: L
authors.lastname: Loufrani
authors.forename: Linda
authors.initials: L
authors.lastname: Grimaud
authors.forename: Dominique
authors.initials: D
authors.lastname: Charue
authors.forename: Joao A
authors.initials: JA
authors.lastname: De Moraes
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Renard
authors.forename: Alain
authors.initials: A
authors.lastname: Tedgui
authors.forename: Chantal M
authors.initials: CM
authors.lastname: Boulanger
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.forename: Olivier P
authors.initials: OP
authors.lastname: Blanc-Brude
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002460:Cell Line; D055252:Cell-Derived Microparticles / Q000378:metabolism / Q000473:pathology*; D042783:Endothelial Cells / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007668:Kidney / Q000098:blood supply* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019700:Thrombospondin 1 / Q000097:blood / Q000378:metabolism
chemical_list: D019700:Thrombospondin 1