A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo.
Platelet adhesion and aggregation at sites of vascular injury is crucial for hemostasis but may lead to arterial occlusion in the setting of atherosclerosis and precipitate diseases such as myocardial infarction. A current hypothesis suggests that platelet glycoprotein (GP) Ib interaction with von Willebrand factor recruits flowing platelets to the injured vessel wall, where subendothelial fibrillar collagens support their firm adhesion and activation. However, so far this hypothesis has not been tested in vivo. Here, we demonstrate by intravital fluorescence microscopy of the mouse carotid artery that inhibition or absence of the major platelet collagen receptor, GPVI, abolishes platelet-vessel wall interactions after endothelial denudation. Unexpectedly, inhibition of GPVI by the monoclonal antibody JAQ1 reduced platelet tethering to the subendothelium by approximately 89%. In addition, stable arrest and aggregation of platelets was virtually abolished under these conditions. Using different models of arterial injury, the strict requirement for GPVI in these processes was confirmed in GPVI-deficient mice, where platelets also failed to adhere and aggregate on the damaged vessel wall. These findings reveal an unexpected role of GPVI in the initiation of platelet attachment at sites of vascular injury and unequivocally identify platelet-collagen interactions (via GPVI) as the major determinant of arterial thrombus formation.
Massberg
Steffen
S
Deutsches Herzzentrum und 1. Medizinische Klinik, Technische Universität München, D-80636 München, Germany.
Gawaz
Meinrad
M
Grüner
Sabine
S
Schulte
Valerie
V
Konrad
Ildiko
I
Zohlnhöfer
Dietlind
D
Heinzmann
Ulrich
U
Nieswandt
Bernhard
B
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology*; D002339:Carotid Arteries / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010974:Platelet Aggregation; D010980:Platelet Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014947:Wounds and Injuries / Q000473:pathology
D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D003094:Collagen