Flow sensing in the cardiovascular system

• HS-PG is flow sensor at blood–endothelium interface and in the subendothelial matrix.
• Na+- and Ca2+-induced conformational changes of HS-PG regulate sensor sensitivity.
• HS-PG causes vasodilatation/vaso-constriction with increasing/decreasing blood flow.
• Endothelial dysfunction/arteriosclerosis impairs sensor function and vasodilatation.
• Synde can preferably responds to low shear rates, perlecan to high shear rates.

BackgroundThis contribution deals with chemical processes at the biological membranes of endothelial cells in blood vessels. A basic observation is that the intensity of blood flow navigates the vascular width through a negative feedback circle. When the blood flow increases, the vessels become wider; when it decreases the vascular smooth muscle cells contract. The anionic polyelectrolyte heparan sulfate proteoglycan (HS-PG) reacts to the shear stress generated by the flowing blood. In the present investigation, this naturally occurring biosensor is characterized in more detail, which is crucially involved in the regulation of peripheral blood flow and organ perfusion. A dysfunction of this sensor can lead to organ insufficiency, hypertension and arteriosclerosis.MethodsEllipsometry, surface force and transient absorption spectra (TAS) measurements were performed on native HS-PG in order to develop an in vitro molecular flow sensor model close to the physiological scenario. Flow-dependent tension was determined in human coronary arteries obtained during heart transplantations. Nontreated, intact preparations were compared to deendothelialized vascular segments and to preparations incubated in a low-concentrated trypsin solution. Trypsination led to shedding of the ectodomain of the transmembrane HS/CS proteoglycan syndecan and to disintegration of the subendothelial matrix.Results and discussionThe ellipsometry, surface force and TAS investigations impressively showed that HS-PG adsorbed to a hydrophobic silica surface assumes the in vivo configuration that is strongly influenced by Na+ and Ca2+ ions. The adsorption occurs via its hydrophobic transmembrane protein moiety, which acts as an anchor for this macromolecule. Thus, the orientation of the sensor is similar to that in the endothelial cell membrane. Flow induces a shear stress-dependent conformational transition to the unfurled filament structure state through which additional anionic binding sites are released. Na+ ions from the blood can bind, triggering the signal transduction chain for vasodilatation. Decrease in flow effects through innermolecular elastic recoil forces an entropic coiling, the release of Na+ ions and thus an interruption of the signal chain. Vasoconstriction is the consequence. Ca2+ ions have a high affinity constant for proteoglycans, eliciting a shortening of the helical advance of heparan sulfate chains and impairing sensor sensitivity. Moreover, Ca2+ induces a conformational change and compaction of HS-PG, which requires several minutes to complete.In the second part of this work, the molecular properties of the flow sensor are applied to the flow-dependent regulation of human coronary arteries and its impairment under the clinical aspect of arteriosclerosis. Normal coronaries show vasodilatation with increasing flow rate which is strongly reduced upon both endothelium removal and arteriosclerosis. Through incubation of the blood vessel segments in low-dose trypsin-Krebs solution for a short time, we succeeded in quantifying the exact contribution of HS-PG in the endothelial cell membrane (syndecan, endothelial sensor) and of HS-PG in the extracellular matrix (perlecan, matrix sensor) to flow-dependent vascular reactivity.ConclusionViscoelastic and polyelectrolytic HS-PGs integrated into the membrane of vascular endothelial cells and the extracellular matrix serve as flow sensors. These biosensor macromolecules respond to shear stress by a conformational change. Under in vivo conditions, the membrane integral syndecan primarily responds to low shear rates, while matrix-anchored perlecan reacts preferably to high shear rates.

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