文章基本信息

标题：Platelet integrins exhibit anisotropic mechanosensing and harness piconewton forces to mediate platelet aggregation
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作者：Yun Zhang ; Yongzhi Qiu ; Aaron T. Blanchard 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2018
卷号：115
期号：2
页码：325-330
DOI：10.1073/pnas.1710828115
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Platelet aggregation at the site of vascular injury is essential in clotting. During this process, platelets are bridged by soluble fibrinogen that binds surface integrin receptors. One mystery in the mechanism of platelet aggregation pertains to how resting platelets ignore soluble fibrinogen, the third most abundant protein in the bloodstream, and yet avidly bind immobile fibrinogen on the surface of other platelets at the primary injury site. We speculate that platelet integrins are mechanosensors that test their ligands across the platelet–platelet synapse. To investigate this model, we interrogate human platelets using approaches that include the supported lipid bilayer platform as well as DNA tension sensor technologies. Experiments suggest that platelet integrins require lateral forces to mediate platelet–platelet interactions. Mechanically labile ligands dampen platelet activation, and the onset of piconewton integrin tension coincides with calcium flux. Activated platelets display immobilized fibrinogen on their surface, thus mediating further recruitment of resting platelets. The distribution of integrin tension was shown to be spatially regulated through two myosin-signaling pathways, myosin light chain kinase and Rho-associated kinase. Finally, we discovered that the termination of integrin tension is coupled with the exposure of phosphatidylserine. Our work reveals the highest spatial and temporal resolution maps of platelet integrin mechanics and its role in platelet aggregation, suggesting that platelets are physical substrates for one another that establish mechanical feedback loops of activation. The results are reminiscent of mechanical regulation of the T-cell receptor, E-cadherin, and Notch pathways, suggesting a common feature for signaling at cell junctions.
关键词：platelets ; integrin ; mechanobiology ; molecular tension sensors