Flow sensing at the endothelial cell membrane-blood interface

Abstract

Through depolarization of the vascular smooth muscle cells, an incrase in blood pressure causes a transmembrane Ca 2+ inward current which leads to contraction. In a negative feedback circle, the Ca 2+ influx effects a stimulation of the Ca 2+ activatable K + channel, the open state probability of which increases. The resulting membrane hyperpolarization produces a vasorelaxation. This smooth muscle relaxation is supported by the blood flow velocity augmented through the vasoconstriction. Via enhanced shear forces at the blood-endothelium interface, the increased flow rate leads to a flow-dependent vasodilatation. All the three mechanisms are feedback-coupled and adapt the vascular width to the actual circulation demands. Under pathophysiological conditions, e.g. in arteriosclerosis, the flow-dependent dilatation may be blunted or even reversed to a flow-dependent constriction. One reason for this is an impaired flow sensor function which, through calcification of certain oversulfated domains, loses its sensitivity to flow and blood sodium. The flow-dependent dilatation is controlled by a flow sensor at the endothelium/blood interface. Presumably, the flow sensor is identical with the integral membrane protein heparan sulfate proteoglycan (syndecan) of endothelial cells, which is a viscoelastic anionic polyelectrolyte. The biopolymer undergoes a shear stress-dependent conformational change with increasing flow from a random coil to an unfurled filament-helix structure. Thereby, Na + ions from the blood are bound to binding sites hidden before, and which, after counterion migration along the polysaccharide chain and transmembrane Na + influx, carry on the signal transduction in the endothelial cell for a vasodilatory vessel reaction. Reduction in flow causes, based on the elastic recoil forces of the biosensor proteoheparan sulfate, an entropic coiling again, the release of Na + ions to the blood and thus an interruption of the signal transduction chain. In 23Na + nuclear magnetic resonance experiments, the shear stress-dependent, reversible Na + binding to the biopolyelectrolyte was demonstrated. Morcover, it appeared that Ca 2+ ions in the physiological concentration range effect a conformational change in the biosensor macromolecules which was confirmed by surface force and ellipsometry measurements. The biosensor adsorbed onto a hydrophobic surface exhibits a spatial configuration similar to the one at the endothelial cell membrane so that a simulation was possible of the interaction of the different ion species in the blood with the macromolecule. A shortening of the heparan sulfate chains through Ca 2+ ions seems to form the basis for a sensitivity adjustment in the sensor. On the other hand, the ellipsometry investigations supported the observation in isolated vessel segments that the shear stress-linked vasodilatation is strongly Na + -dependent. Proteoheparan sulfate was shown to sense primarily Na + as “first messenger” in the signal transduction chain.