title: Importance of temporal flow gradients and integrin alphaIIbbeta3 mechanotransduction for shear activation of platelets.
abstract: Disturbances of blood flow play an important role in promoting platelet activation and arterial thrombus formation in stenosed, injured, atherosclerotic arteries. To date, glycoprotein Ib (GPIb) has been considered the primary platelet mechanosensory receptor, responding to increased shear with enhanced adhesive and signaling function. We demonstrate here that von Willebrand factor-GPIb interaction is inefficient at inducing platelet activation even when platelets are exposed to very high wall shear stresses (60 dyn/cm(2)). Rapid platelet activation under flow was only observed under experimental conditions in which transiently adherent platelets were exposed to sudden accelerations in blood flow. Platelet responsiveness to temporal shear gradients was integrin alpha(IIb)beta(3)-dependent and occurred only on a von Willebrand factor substrate, as platelets forming integrin alpha(IIb)beta(3) adhesive contacts with immobilized fibrinogen were unresponsive to sudden increases in shear. The calcium response induced by temporal shear gradients was distinct from previously identified integrin alpha(IIb)beta(3) calcium responses in terms of its transient nature, its requirement for platelet co-stimulation by the P2Y(1) purinergic ADP receptor, and its dependence on the influx of extracellular calcium. Our studies demonstrate a key role for temporal shear gradients in promoting platelet activation. Moreover, they define for the first time the involvement of P2Y receptors in integrin mechanotransduction.
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Educational Precinct, Prahran, Victoria 3181, Australia.
authors.forename: Isaac
authors.initials: I
authors.lastname: Goncalves
authors.forename: Warwick S
authors.initials: WS
authors.lastname: Nesbitt
authors.forename: Yuping
authors.initials: Y
authors.lastname: Yuan
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005340:Fibrinogen / Q000737:chemistry; D006801:Humans; D016023:Integrins / Q000378:metabolism; D015539:Platelet Activation; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry* / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D016023:Integrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D040201:Platelet Membrane Glycoprotein IIb; D014841:von Willebrand Factor; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D002118:Calcium