Flow Regulation of Vascular Tone: Its Sensitivity to Changes in Sodium and Calcium

Our hypothesis is that flow-through hydraulic drag or shear stresses the extracellular elements in the vascular wall. When the endothelium is intact, this results in the release of endothelium-derived relaxing factor and other substances, eg, prostanoids, from the endothelium. As in some reports, after inhibition of nitric oxide synthase, flow effects are still observed although diminished; the shear effect is extended mechanically to the subendothelial tissues. Shear causes conformational changes in the glycosaminoglycans by extending them from a randomly coiled aggregated state to a more elongated condition along the line of flow. This elongation and the consequent exposure of an increased number of cationic binding sites on the glycosaminoglycans lead to changes in sodium binding. The extent of the conformational change is influenced by the concentration of calcium, an ion that not only competes with sodium at specific binding sites but possibly cross-links the polysaccharide chains of the protein saccharide complex. These complex interactions might account for the cooperative, nonantagonistic interaction of sodium and calcium over the physiological concentration range. Sodium binding is influenced by changes in external sodium concentration, and this presumably accounts for the sodium sensitivity of the flow response. Although glycosaminoglycans are possibly the most studied in this regard, they are not the only candidates. Other extracellular proteins, either in conjunction with glycosaminoglycans or independently, might be involved. By mechanisms not yet identified, these changes are signaled to the cell. We have proposed that in part, at any rate, this may be related to the sodium concentration gradient.