Soluble glycoprotein VI dimer inhibits platelet adhesion and aggregation to the injured vessel wall in vivo.
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.
Massberg
Steffen
S
Klinikum rechts der Isar, 1. Medizinische Klinik, Technische Universität München, D-81675 München, Germany. massberg@dhm.mhn.de
Konrad
Ildiko
I
Bültmann
Andreas
A
Schulz
Christian
C
Münch
Götz
G
Peluso
Mario
M
Lorenz
Michael
M
Schneider
Simon
S
Besta
Felicitas
F
Müller
Iris
I
Hu
Bin
B
Langer
Harald
H
Kremmer
Elisabeth
E
Rudelius
Martina
M
Heinzmann
Ulrich
U
Ungerer
Martin
M
Gawaz
Meinrad
M
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
D007141:Immunoglobulin Fc Fragments; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D003094:Collagen