title: Flow-driven assembly of VWF fibres and webs in in vitro microvessels.
abstract: Several systemic diseases, including thrombotic thrombocytopenic purpura, manifest much of their pathology through activation of endothelium and thrombotic occlusion of small blood vessels, often leading to multi-organ failure and death. Modelling these diseases is hampered by the complex three-dimensional architecture and flow patterns of the microvasculature. Here, we employ engineered microvessels of complex geometry to examine the pathological responses to endothelial activation. Our most striking finding is the capacity of endothelial-secreted von Willebrand factor (VWF) to assemble into thick bundles or complex meshes, depending on the vessel geometry and flow characteristics. Assembly is greatest in vessels of diameter ≤300 μm, with high shear stress or strong flow acceleration, and with sharp turns. VWF bundles and webs bind platelets, leukocytes and erythrocytes, obstructing blood flow and sometimes shearing passing erythrocytes. Our findings uncover the biophysical requirements for initiating microvascular thrombosis and suggest mechanisms for the onset and progression of microvascular diseases.
authors.affiliation: 1] Department of Bioengineering, University of Washington, Seattle, Washington 98109, USA [2] Center of Cardiovascular Biology, Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Bloodworks Northwest Research Institute, Seattle, Washington 98102, USA.
authors.forename: Junmei
authors.initials: J
authors.lastname: Chen
authors.affiliation: 1] Bloodworks Northwest Research Institute, Seattle, Washington 98102, USA [2] Departments of Medicine (Hematology), Biochemistry, and Mechanical Engineering, University of Washington, Seattle, Washington 98195, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: López
mesh_terms: D001792:Blood Platelets / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000378:metabolism; D008833:Microcirculation; D055806:Microvessels / Q000378:metabolism*; D011697:Purpura, Thrombotic Thrombocytopenic / Q000378:metabolism*; D013314:Stress, Mechanical; D023822:Tissue Engineering; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor