title: Glycoprotein Ib-IX-V Complex Transmits Cytoskeletal Forces That Enhance Platelet Adhesion.
abstract: Platelets bind to exposed vascular matrix at a wound site through a highly specialized surface receptor, glycoprotein (GP) Ib-IX-V complex, which recognizes von Willebrand factor (VWF) in the matrix. GPIb-IX-V is a catch bond for it becomes more stable as force is applied to it. After attaching to the wound site, platelets generate cytoskeletal forces to compact and reinforce the hemostatic plug. Here, we evaluated the role of the GPIb-IX-V complex in the transmission of cytoskeletal forces. We used arrays of flexible, silicone nanoposts to measure the contractility of individual platelets on VWF. We found that a significant proportion of cytoskeletal forces were transmitted to VWF through GPIb-IX-V, an unexpected finding given the widely held notion that platelet forces are transmitted exclusively through its integrins. In particular, we found that the interaction between GPIbα and the A1 domain of VWF mediates this force transmission. We also demonstrate that the binding interaction between GPIbα and filamin A is involved in force transmission. Furthermore, our studies suggest that cytoskeletal forces acting through GPIbα are involved in maintaining platelet adhesion when external forces are absent. Thus, the GPIb-IX-V/VWF bond is able to transmit force, and uses this force to strengthen the bond through a catch-bond mechanism. This finding expands our understanding of how platelets attach to sites of vascular injury, describing a new, to the best of our knowledge, mechanism in which the catch bonds of GPIb-IX-V/VWF can be supported by internal forces produced by cytoskeletal tension.
authors: Department of Mechanical Engineering, University of Washington, Seattle, Washington.
authors: Shirin
authors: S
authors: Feghhi
authors: BloodWorks Northwest Research Institute, Seattle, Washington.
authors: Adam D
authors: AD
authors: Munday
authors: Department of Mechanical Engineering, University of Washington, Seattle, Washington.
authors: Wes W
authors: WW
authors: Tooley
authors: Department of Mechanical Engineering, University of Washington, Seattle, Washington.
authors: Shreya
authors: S
authors: Rajsekar
authors: BloodWorks Northwest Research Institute, Seattle, Washington.
authors: Adriane M
authors: AM
authors: Fura
authors: BloodWorks Northwest Research Institute, Seattle, Washington.
authors: John D
authors: JD
authors: Kulman
authors: Department of Mechanical Engineering, University of Washington, Seattle, Washington; Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington; Department of Biochemistry, University of Washington, Seattle, Washington; BloodWorks Northwest Research Institute, Seattle, Washington.
authors: Jose A
authors: JA
authors: López
authors: Department of Mechanical Engineering, University of Washington, Seattle, Washington; Department of Bioengineering, University of Washington, Seattle, Washington; Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington. Electronic address: nsniadec@uw.edu.
authors: Nathan J
authors: NJ
authors: Sniadecki
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003599:Cytoskeleton / Q000378:metabolism*; D064448:Filamins / Q000378:metabolism; D006801:Humans; D055595:Mechanical Phenomena; D010973:Platelet Adhesiveness; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*
chemical_list: D064448:Filamins; D019038:Platelet Glycoprotein GPIb-IX Complex