Macromolecular Studies of the Dynamic Structure and Mechanical Properties of the Endothelial Surface Layer
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Date
2006-08-03T15:27:26Z
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Johns Hopkins University
Abstract
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
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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.