Firewall function of the endothelial glycocalyx in the regulation of sodium homeostasis

Abstract

Plasma sodium, slightly above normal and in presence of aldosterone, stiffens vascular endothelium and reduces nitric oxide release with the consequence of endothelial dysfunction. This process is mediated by epithelial sodium channels (ENaC) and, most likely, the endothelial Na(+)/K(+)-ATPase. Both, ENaC and Na(+)/K(+)-ATPase, are located in the plasma membrane of endothelial cells and embedded in the endothelial glycocalyx (eGC). This negatively charged biopolymer is directly exposed to the blood stream and selectively buffers sodium ions. We hypothesize that the glycocalyx could interfere with endothelial sodium transport when extracellular sodium varies in the physiological range. Therefore, we modeled the endothelial cell as a pump-leak system measuring changes of intracellular sodium in cultured human endothelial cells. Experiments were performed under low/high extracellular sodium conditions before and after enzymatic eGC removal, and with inhibition of Na(+)/K(+)-ATPase and ENaC, respectively. Three major observations were made: (1) eGC removal by heparinase treatment facilitates sodium to enter/exit the endothelial cells. (2) The direction of net sodium movement across the endothelial plasma membrane depends on the concentration of extracellular sodium which regulates both the Na(+)/K(+)-ATPase and ENaC activity. (3) Removal of eGC and inhibition of sodium transport modify the electrical resistance of endothelial cells. We conclude that the eGC serves as a potential "firewall" preventing uncontrolled access of sodium to the pump-leak system of the endothelial cell. After eGC removal, sodium access to the system is facilitated. Thus the pump-leak system could be regulated by ambient sodium and control vascular permeability in pathophysiological conditions.

Role of the Vascular Wall in Sodium Homeostasis and Salt Sensitivity

“…Enzymatic removal of the ESL has been shown to facilitate EnNaC-mediated sodium transport into the endothelial cells, which led to increased endothelial stiffness. 48,50 These results indicate that an intact ESL functions as a barrier to control EnNaC-mediated sodium transport.…”

“…Enzymatic removal of the ESL has been shown to facilitate EnNaC-mediated sodium transport into the endothelial cells, which led to increased endothelial stiffness. 48,50 These results indicate that an intact ESL functions as a barrier to control EnNaC-mediated sodium transport.On the basis of the data as discussed above, the ESL seems to affect sodium homeostasis by functioning as an intravascular buffer for sodium as well as a barrier protecting the endothelial cell against EnNaC-mediated sodium uptake (Figure 1). An intact ESL having sufficient buffering function would, therefore, be able to transiently store osmotically inactive sodium, whereas a perturbed ESL cannot.…”

“…After discovery of the epithelial sodium channel on the endothelial luminal surface (EnNaC) next to its known presence on the apical plasma membrane of epithelia, it was shown that this EnNaC regulates endothelial nanomechanics and subsequently affects NO production. [47][48][49][50] By enhancing sodium influx, the EnNaC increases mechanical stiffness of the endothelial cellular cortex. 48,49 The stiffness of this 50-to 100-nm layer, which mainly consists of actin filaments, subsequently modulates endothelial NO synthase activity and NO production, where an increasing stiffness attenuates NO production.…”

“…A rise in plasma sodium concentration increases EnNaC density, which in turn, increases sodium uptake, stiffens the endothelial cellular cortex, and subsequently, leads to diminished NO production. 50 An increase in sodium delivery to the endothelial cell as a result of an increase in sodium intake could, therefore, lead to an increase in vascular tone. These experimental findings are consistent with studies in humans, in which dietary sodium restriction has been shown to improve macrovascular and microvascular endothelial function by an enhanced bioavailability of NO directly induced by the low sodium diet.…”

The Initial Common Pathway of Inflammation, Disease, and Sudden Death

“…Esitashvili and Msuknishvili observed an increase in blood surface tension during acute myocardial infarction in humans [54]. Electrostatic interactions and interfacial charge regulation of biomembranes is a focus of intense ongoing research [65][66][67][73][74][75][76][77][78][79][80][81]. Fiszer-Kierzkowska recently suggested that cationic liposomes may not be suitable vehicles for gene transfection, given that they produced apoptosis and aggregation of misfolded proteins and/or fluidity changes of cellular membranes [82].…”