title: Platelet GPVI binds to collagenous structures in the core region of human atheromatous plaque and is critical for atheroprogression in vivo.
abstract: Platelet adhesion to the atherosclerotic vascular wall induces thrombosis and boosters vascular inflammation and atheroprogression. In the present study we studied the binding of the platelet collagen receptor glycoprotein (GP) VI to human atherosclerotic plaques (AP) and the role of GPVI-mediated platelet adhesion for atheroprogression. Soluble GPVI-Fc fusion protein bound to immobilized collagen type I, collagen type III, and predominantly to the core region of human carotid atheromatous plaques. The pattern of GPVI-Fc binding was similar to the immunostaining pattern of collagen type III and differed from the immunostaining of collagen type I, which was more intense in the cap than in the core. Plaque-induced platelet aggregation in stirred blood and platelet adhesion/aggregate formation under flow were inhibited by the anti-GPVI monoclonal antibody 5C4 or by pretreatment of plaques with anti-collagen type I and anti-collagen type III antibody, or GPVI-Fc. However, there was no correlation between GPVI-Fc binding and platelet aggregating activity of individual plaques. GPVI bound also to atherosclerotic arteries of ApoE-deficient mice in vivo as assessed by small animal positron emission tomography (PET). Prolonged administration of soluble GPVI attenuated atheroprogression in ApoE-deficient mice. In humans, GPVI binding to collagenous type I and type III structures of the plaque core region mediates plaque-induced platelet adhesion and aggregation, but GPVI binding is not the sole platelet-activating determinant of plaques. In mice, GPVI-mediated platelet adhesion to the atherosclerotic vascular wall is involved in atheroprogression in vivo. Taken together, our data suggests that GPVI is a relevant target to prevent atherothrombotic events and atheroprogression.
authors.affiliation: Deutsches Herzzentrum und 1. Medizinische Klinik Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schulz
authors.forename: Sandra
authors.initials: S
authors.lastname: Penz
authors.forename: Christof
authors.initials: C
authors.lastname: Hoffmann
authors.forename: Harald
authors.initials: H
authors.lastname: Langer
authors.forename: Angelika
authors.initials: A
authors.lastname: Gillitzer
authors.forename: Simon
authors.initials: S
authors.lastname: Schneider
authors.forename: Richard
authors.initials: R
authors.lastname: Brandl
authors.forename: Stefan
authors.initials: S
authors.lastname: Seidl
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Bernd
authors.initials: B
authors.lastname: Pichler
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Stellos
authors.forename: Tanja
authors.initials: T
authors.lastname: Schönberger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Siess
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D003094:Collagen / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010973:Platelet Adhesiveness; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D001057:Apolipoproteins E; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D003094:Collagen