Collagen Fibrils in DDR1 Deficient Mice Modulate Platelet Adhesion
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. Department of Biomedical Engineering Honors Theses; 2017
Platelet adhesion to the sub-endothelial collagen is primarily mediated through the binding of platelet receptors, such as glycoprotein VI (GPVI) to collagen and GPIb to collagen-bound von Willebrand factor (VWF). The role of non-platelet derived receptors in modulating platelet-collagen interaction is not well-understood. Discoidin domain receptor 1 (DDR1) is a collagen-binding receptor tyrosine kinase that inhibits collagen fibril formation and disrupts the native banded structure of collagen fibers. We have recently shown how the adventitia of DDR1 KO mice exhibited collagen fibrils with larger diameters, and an increase in the depth of D-periods as compared to their wild type (WT) littermates. The purpose of this study was to examine if changes in the collagen fibril structure in the DDR1 KO vessel wall impact platelet adhesion and the extent to which this is modulated by VWF vs. GPVI. Human platelet-rich plasma was incubated, both with and without VWF or GPVI inhibitors, over aortic cross sections from DDR1 KO and WT mice under static conditions. Platelet adhesion to the adventitia of the vessel wall was evaluated using indirect immunofluorescence microscopy. Quantitative analysis of platelet adhesion to the adventitia was carried out by analyzing the area of platelet particles per unit area of collagen. The results displayed that DDR1 KO mice had greater platelet adhesion to adventitia than WT. Also, DDR1 knockout mice showed greater inhibition than the WT mice in the presence of VWF inhibitors. We thus elucidate that changes in collagen fibril ultrastructure impact platelet-collagen adhesion by altering the number of GPVI binding sites available on collagen fibrils. This knowledge is important for pathological conditions, such as atherosclerosis and aneurysms, where collagen is extensively remodeled, and could lead to altered collagen fibril structure and thrombogenic events.
Academic Major: Biomedical Engineering