title: Soluble glycoprotein VI dimer inhibits platelet adhesion and aggregation to the injured vessel wall in vivo.
abstract: Platelet-collagen interactions play a fundamental role in the process of arterial thrombosis. The major platelet collagen receptor is the glycoprotein VI (GPVI). Here, we determined the effects of a soluble dimeric form of GPVI on platelet adhesion in vitro and in vivo. We fused the extracellular domain of GPVI with the human immunoglobulin Fc domain. The soluble dimeric form of GPVI (GPVI-Fc) specifically bound to immobilized collagen. Binding of GPVI-Fc to collagen was inhibited competitively by soluble GPVI-Fc, but not control Fc lacking the external GPVI domain. GPVI-Fc inhibited the adhesion of CHO cells that stably express human GPVI and of platelets on collagen and attenuated thrombus formation under shear conditions in vitro. To test the effects of GPVI-Fc in vivo, arterial thrombosis was induced in the mouse carotid artery, and platelet-vessel wall interactions were visualized by intravital fluorescence microscopy. Infusion of GPVI-Fc but not of control Fc virtually abolished stable arrest and aggregation of platelets following vascular injury. Importantly, GPVI-Fc but not control Fc, was detected at areas of vascular injury. These findings further substantiate the critical role of the collagen receptor GPVI in the initiation of thrombus formation at sites of vascular injury and identify soluble GPVI as a promising antithrombotic strategy.
authors.affiliation: Klinikum rechts der Isar, 1. Medizinische Klinik, Technische Universität München, D-81675 München, Germany. massberg@dhm.mhn.de
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Ildiko
authors.initials: I
authors.lastname: Konrad
authors.forename: Andreas
authors.initials: A
authors.lastname: Bültmann
authors.forename: Christian
authors.initials: C
authors.lastname: Schulz
authors.forename: Götz
authors.initials: G
authors.lastname: Münch
authors.forename: Mario
authors.initials: M
authors.lastname: Peluso
authors.forename: Michael
authors.initials: M
authors.lastname: Lorenz
authors.forename: Simon
authors.initials: S
authors.lastname: Schneider
authors.forename: Felicitas
authors.initials: F
authors.lastname: Besta
authors.forename: Iris
authors.initials: I
authors.lastname: Müller
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Harald
authors.initials: H
authors.lastname: Langer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Martina
authors.initials: M
authors.lastname: Rudelius
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heinzmann
authors.forename: Martin
authors.initials: M
authors.lastname: Ungerer
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000502:physiology*; D016466:CHO Cells; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology*; D003001:Cloning, Molecular; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D019281:Dimerization; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D010976:Platelet Count; D010980:Platelet Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D012212:Rheology; D012995:Solubility; D013927:Thrombosis
chemical_list: D007141:Immunoglobulin Fc Fragments; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D003094:Collagen