Adhesion of human and mouse platelets to collagen under shear: a unifying model.
There is presently confusion as to the roles of alpha2beta1 and GPVI in supporting platelet adhesion and aggregate formation on collagen at intermediate/high shear. Recent studies have reported essential, partial, or dispensable roles for either receptor in supporting these events, and the possibility that there may be fundamental differences between their roles in human and mouse platelets has been proposed. Further, the recent recognition that Src family tyrosine kinases contribute to signaling by alpha2beta1 and other adhesive receptors, in addition to GPVI, has added to this debate. The present study compares the roles of alpha2beta1, GPVI, and Src-dependent kinases in supporting adhesion and aggregation in human and mouse platelets in whole blood using blocking antibodies, mutant mice, and a novel inhibitor of Src kinases, PD0173952, which is effective in plasma. The results demonstrate that the fundamental processes of adhesion and aggregate formation are conserved in mice and human platelets and that two mechanisms of stable adhesion and activation on collagen exist. These can be distinguished by the contributions of GPVI and alpha2beta1, with GPVI-mediated platelet activation either preceding or following integrin-mediated adhesion. The relative contribution of each pathway depends on environmental conditions and may also reflect platelet heterogeneity. These observations form the basis of a unifying two-state model of platelet adhesion and aggregate formation on collagen that is conserved between human and mouse platelets.
Auger
Jocelyn M
JM
Centre for Cardiovascular Sciences, Division of Medical Sciences, Institute of Biomedical Research, The Medical School, University of Birmingham, Edgbaston, Birmingham, UK. jma299@bham.ac.uk
Kuijpers
Marijke J E
MJ
Senis
Yotis A
YA
Watson
Steve P
SP
Heemskerk
Johan W M
JW
D000818:Animals; D003094:Collagen / Q000378:metabolism*; D006801:Humans; D038982:Integrin alpha2beta1 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010973:Platelet Adhesiveness / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D012212:Rheology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D038982:Integrin alpha2beta1; D047908:Intracellular Signaling Peptides and Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; C015482:protein kinase modulator; D003094:Collagen; D019061:src-Family Kinases