Some Aspects in Mechano-Biology of Platelet and Leukocyte in Blood Flows

Abstract

For hemostasis and thrombosis, some proteins, such as Von Willebrand Factor (VWF, a multimeric plasma glycoprotein synthesized in endothelial cells and megakaryocytes and secreted to circulation or attached to endothelial cells), the metalloprotease ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13), P-selectin (one of three selectin family members with a N-terminal C-type lectin domain, an epidermal growth factor (EGF)-like module, a series of consensus repeat (CR) units, a transmembrane segment and a short cyto-plasmic domain) and β2 integrin. In adhesion and aggregation of circulating platelets towards to the sites of vascular injury, VWF on vascular wall captures and activates the circulating platelets through interaction with platelet receptor glycoprotein Ibα (GPIbα). The activated platelets will secrete P-selectin, mediating flowing leukocytes to be captured first to and then rolled on the platelets. Activation of β2 integrin on leukocytes makes the rolling cells slow down and adhere firmly to platelet. Pathological hemodynamic environment may cause platelet-induced inflammation overreaction of leukocytes, leading to mechanical instability of thrombotic plaque. Above mentioned events all are referred to their respective un-well known mechano-chemistry processes. For better understanding on the mechano-chemistry mechanism of interaction of leukocyte with platelet under flows, we have investigated the force-dependent Structure-function of VWF-A domain, force-regulated cleavage of A2 domain of von Willebrand factor (vWF) by ADAMTS13, P-selectin secretion from activated platelet, and P-selectin-mediated Activation of β2 integrin on leukocytes under shear stresses, and so on through AFM and flow chamber experiments and molecular dynamics simulation. Our data showed that, these events mentioned above were biphasic force-dependent. Increasing force stabilizes the globular VWF-A conformation first and then makes it become a spread one with higher affinity with platelet receptor glycoprotein Ibα (GPIbα), the force-regulated cleavage of VWF-A2 domain by ADAMTS13 maybe closely related to the induced-fit of ADMATS13 and VWF-A2, Force triggers and quickens P-selectin-induced Activation of β2 integrin on leukocytes.