Macromolecular Studies of the Dynamic Structure and Mechanical Properties of the Endothelial Surface Layer
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The endothelial surface layer (ESL) is a micron-scale macromolecular lining of the luminal side of blood vessels, composed of proteoglycans, glycoproteins, polysaccharides and plasma proteins in dynamic equilibrium. Its physiological implications include blood flow and microvascular permeability regulation, and active participation in mechanotransduction, stress regulation, coagulation, inflammation and angiogenesis. The ESL dynamic structure and mechanical properties are primarily controlled by its composition and topology on macromolecular scales and are decisive for most ESL functions. In this thesis, theoretical research on the glycocalyx was performed using computer simulation and modeling. A topological model was created containing three basic macromolecular elements: branched proteoglycans, linear polysaccharides, and plasma proteins, and studied using non-equilibrium MD simulations. The effects of composition and shear flow were investigated initially for permanently-bound ESL. Proteoglycans were not sufficient to efficiently screen the shear flow from the cell surface. ESL lacking plasma proteins was much less dense than the protein-containing ESL. Low to moderate shear flows had negligible effect on the glycocalyx structure. High shear flows provoked ESL thinning and pronounced stretching in the flow direction. Self-assembling ESL with associating proteins in equilibrium with the bulk was next investigated. The plasma protein distribution was found sensitive to the polysaccharide-protein interaction energy but not affected by shear flow. The protein diffusion in the bulk and in the ESL was evaluated and the average lifetimes of the polysaccharide-protein complexes were iii estimated. The ESL dynamic structure and the protein distribution were observed for different total protein concentrations. For weak polysaccharide-protein interactions, the gradual decrease of total protein in the system resulted in drastic decrease of the ESLassociated amount. For strong interactions there was significant residual protein in the ESL even for negligibly low protein concentrations in the plasma. Finally, a theoretical model of the self-assembling ESL was created based on established models for tethered and associating polymers. Equilibrium and steady-state ESL properties were calculated including height, osmotic pressure, deformation under flow, and the mean number of coils per chain in the ESL as a function of various physicochemical parameters. The model predictions were found to be broadly consistent with the simulation results.