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1.  Blood Pressure and Amiloride-Sensitive Sodium Channels in Vascular and Renal Cells 
Nature reviews. Nephrology  2014;10(3):146-157.
This review is focused on the expression and regulation of amiloride-sensitive sodium channels in the epithelial cells of the aldosterone-sensitive distal nephron (ENaC) and amiloride-sensitive sodium channel activity in vascular endothelial and smooth muscle cells. Guyton’s hypothesis stated that blood pressure control is critically dependent on vascular tone and fluid handling by the kidney. With the study of Mendelian forms of hypertension and their corresponding transgenic mouse models, the main components of the aldosterone- and angiotensin-dependent sodium transporters have been identified over the past 20 years. Proteolytic processing of the ENaC external domain, and inhibition by increased sodium concentrations are important features of the ENaC complexes expressed in the distal nephron. In contrast, amiloride-sensitive sodium channels expressed in the vascular system are activated by increased external sodium concentrations, resulting in changes in the mechanical properties and function of endothelial cells. Mechano-sensitivity and shear stress affect both epithelial and vascular sodium channel activity. The synergistic effects and complementary regulation of the epithelial and vascular systems are consistent with the Guytonian model of volume and blood pressure regulation, and may reflect sequential evolution of the two systems. The integration of vascular tone, renal perfusion and regulation of renal sodium reabsorption is the central underpinning of the Guytonian model. We summarize the recent evidence in this review that describes the central role of amiloride-sensitive sodium channels in the efferent (e.g., vascular) and afferent (e.g., epithelial) arms of this homeostatic system.
PMCID: PMC4137491  PMID: 24419567
2.  Nanomechanics of vascular endothelium 
Cell and Tissue Research  2014;355(3):727-737.
The mechanical characteristics of endothelial cells reveal four distinct compartments, namely glycocalyx, cell cortex, cytoplasm and nucleus. There is accumulating evidence that endothelial nanomechanics of these individual compartments control vascular physiology. Depending on protein composition, filament formation and interaction with cross-linker proteins, these four compartments determine endothelial stiffness. Structural organization and mechanical properties directly influence physiological processes such as endothelial barrier function, nitric oxide release and gene expression. This review will focus on endothelial nanomechanics and its impact on vascular function.
PMCID: PMC3972433  PMID: 24643677
Endothelium; Mechanics; Glycocalyx; Cortex; Nucleus
3.  Nanomechanics of the Endothelial Glycocalyx in Experimental Sepsis 
PLoS ONE  2013;8(11):e80905.
The endothelial glycocalyx (eGC), a carbohydrate-rich layer lining the luminal side of the endothelium, regulates vascular adhesiveness and permeability. Although central to the pathophysiology of vascular barrier dysfunction in sepsis, glycocalyx damage has been generally understudied, in part because of the aberrancy of in vitro preparations and its degradation during tissue handling. The aim of this study was to analyze inflammation-induced damage of the eGC on living endothelial cells by atomic-force microscopy (AFM) nanoindentation technique. AFM revealed the existence of a mature eGC on the luminal endothelial surface of freshly isolated rodent aorta preparations ex vivo, as well as on cultured human pulmonary microvascular endothelial cells (HPMEC) in vitro. AFM detected a marked reduction in glycocalyx thickness (266 ± 12 vs. 137 ± 17 nm, P<0.0001) and stiffness (0.34 ± 0.03 vs. 0.21 ± 0.01 pN/mn, P<0.0001) in septic mice (1 mg E. coli lipopolysaccharides (LPS)/kg BW i.p.) compared to controls. Corresponding in vitro experiments revealed that sepsis-associated mediators, such as thrombin, LPS or Tumor Necrosis Factor-α alone were sufficient to rapidly decrease eGC thickness (-50%, all P<0.0001) and stiffness (-20% P<0.0001) on HPMEC. In summary, AFM nanoindentation is a promising novel approach to uncover mechanisms involved in deterioration and refurbishment of the eGC in sepsis.
PMCID: PMC3835794  PMID: 24278345
4.  Correction: Nanomechanics and Sodium Permeability of Endothelial Surface Layer Modulated by Hawthorn Extract WS 1442 
PLoS ONE  2013;8(7):10.1371/annotation/ac261a1e-0beb-496a-b7ca-b099309776c8.
PMCID: PMC3735856
5.  Determination of erythrocyte sodium sensitivity in man 
Pflugers Archiv  2013;465(10):1459-1466.
Sodium buffer capacity of vascular endothelium depends on an endothelial glycocalyx rich in negatively charged heparan sulfate. It has been shown recently that after the mechanical interaction of blood with heparan sulfate-depleted endothelium, erythrocytes also lose this glycocalyx constituent. This observation led to the conclusion that the vascular sodium buffer capacity of an individual could be derived from a blood sample. A test system (salt blood test (SBT)) was developed based upon the sodium-dependent erythrocyte zeta potential. Erythrocyte sedimentation velocity was measured in isosmotic, biopolymer-supplemented electrolyte solutions of different sodium concentrations. Erythrocyte sodium sensitivity (ESS), inversely related to erythrocyte sodium buffer capacity, was expressed as the ratio of the erythrocyte sedimentation velocities of 150 mM over 125 mM Na+ solutions (ESS = Na+150/Na+125). In 61 healthy individuals (mean age, 23 ± 0.5 years), ESS ranged between 2 and 8. The mean value was 4.3 ± 0.19. The frequency distribution shows two peaks, one at about 3 and another one at about 5. To test whether ESS reflects changes of the endothelial glycocalyx, a cultured endothelial monolayer was exposed for 3 hours to a rhythmically moving blood layer (drag force experiment). When applying this procedure, we found that ESS was reduced by about 21 % when the endothelium was pretreated for 4 days with the glycocalyx protective agent WS 1442. In conclusion, the SBT could possibly serve as an in vitro test system for the evaluation of erythrocyte/vascular salt sensitivity allowing follow-up measurements in the prevention and treatment of vascular dysfunctions.
PMCID: PMC3778990  PMID: 23686295
Erythrocyte glycocalyx; Heparan sulfate; Endothelial glycocalyx; Red blood cell sedimentation velocity; Vascular sodium sensitivity
6.  An emerging concept of vascular salt sensitivity 
Excessive amounts of salt in food, as usually consumed worldwide, affect the vascular system, leading to high blood pressure and premature disabilities. Salt entering the vascular bed after a salty meal is transiently bound to the endothelial glycocalyx, a negatively charged biopolymer lining the inner surface of the blood vessels. This barrier protects the endothelium against salt overload. A poorly-developed glycocalyx increases the salt permeability of the vascular system and the amount of salt being deposited in the body, which affects organ function. A simple test system is now available that evaluates vascular salt sensitivity in humans and identifies individuals who are at risk of salt-induced hypertension. This short review aims to discuss how the underlying basic research can be translated into medical practice and, thus, meaningful health outcomes.
PMCID: PMC3463896  PMID: 23112808
7.  A physiological concept unmasking vascular salt sensitivity in man 
Pflugers Archiv  2012;464(3):287-293.
About one third of the population worldwide is supposed to be salt sensitive which is a major cause for arterial hypertension later in life. For preventive actions it is thus desirable to identify salt-sensitive individuals before the appearance of clinical symptoms. Recent observations suggest that the vascular endothelium consists of two salt-sensitive barriers in series, the glycocalyx that buffers sodium and the endothelial cell membrane that contains sodium channels. Glycocalyx sodium buffer capacity and sodium channel activity are conversely related to each other. For proof of concept, a so-called salt provocation test (SPT) was developed that should unmask vascular salt sensitivity in humans at virtually any age. Nineteen healthy subjects, ranging from 25 to 63 years of age, underwent two series of 1-h blood pressure measurements after acute ingestion of a salt cocktail with or without addition of a sodium channel blocker effective in vascular endothelium. Differential analysis of the changes in diastolic blood pressure (net ∆DP) identified 12 individuals (63 %) as being salt resistant (net ∆DP = −0.05 ± 0.62 mmHg) and seven individuals (37 %) as being salt sensitive (net ∆DP = +6.98 ± 0.75 mmHg). Vascular salt sensitivity was not related to the age of the study participants. It is concluded that the SPT could be useful for identifying vascular salt sensitivity in humans already early in life.
PMCID: PMC3423571  PMID: 22744228
Epithelial sodium channel (ENaC); Amiloride; Hypertension; Endothelial glycocalyx; Salt provocation test
8.  Nanomechanics and Sodium Permeability of Endothelial Surface Layer Modulated by Hawthorn Extract WS 1442 
PLoS ONE  2012;7(1):e29972.
The endothelial glycocalyx (eGC) plays a pivotal role in the physiology of the vasculature. By binding plasma proteins, the eGC forms the endothelial surface layer (ESL) which acts as an interface between bloodstream and endothelial cell surface. The functions of the eGC include mechanosensing of blood flow induced shear stress and thus flow dependent vasodilation. There are indications that levels of plasma sodium concentrations in the upper range of normal and beyond impair flow dependent regulation of blood pressure and may therefore increase the risk for hypertension. Substances, therefore, that prevent sodium induced endothelial dysfunction may be attractive for the treatment of cardiovascular disease. By means of combined atomic force - epifluorescence microscopy we studied the impact of the hawthorn (Crataegus spp.) extract WS 1442, a herbal therapeutic with unknown mechanism of action, on the mechanics of the ESL of ex vivo murine aortae. Furthermore, we measured the impact of WS 1442 on the sodium permeability of endothelial EA.hy 926 cell monolayer. The data show that (i) the ESL contributes by about 11% to the total endothelial barrier resistance for sodium and (ii) WS 1442 strengthens the ESL resistance for sodium up to about 45%. This mechanism may explain some of the vasoprotective actions of this herbal therapeutic.
PMCID: PMC3254622  PMID: 22253842
9.  Salt overload damages the glycocalyx sodium barrier of vascular endothelium 
Pflugers Archiv  2011;462(4):519-528.
Sodium overload stiffens vascular endothelial cells in vitro and promotes arterial hypertension in vivo. The hypothesis was tested that the endothelial glycocalyx (eGC), a mesh of anionic biopolymers covering the surface of the endothelium, participates in the stiffening process. By using a mechanical nanosensor, mounted on an atomic force microscope, height (∼400 nm) and stiffness (∼0.25 pN/nm) of the eGC on the luminal endothelial surface of split-open human umbilical arteries were quantified. In presence of aldosterone, the increase of extracellular sodium concentration from 135 to 150 mM over 5 days (sodium overload) led the eGC shrink by ∼50% and stiffening by ∼130%. Quantitative eGC analyses reveal that sodium overload caused a reduction of heparan sulphate residues by 68% which lead to destabilization and collapse of the eGC. Sodium overload transformed the endothelial cells from a sodium release into a sodium-absorbing state. Spironolactone, a specific aldosterone antagonist, prevented these changes. We conclude that the endothelial glycocalyx serves as an effective buffer barrier for sodium. Damaged eGC facilitates sodium entry into the endothelial cells. This could explain endothelial dysfunction and arterial hypertension observed in sodium abuse.
PMCID: PMC3170475  PMID: 21796337
Endothelium; Aldosterone; Vascular dysfunction; Sodium channel; Sodium
10.  Two barriers for sodium in vascular endothelium? 
Annals of Medicine  2012;44(Suppl 1):S143-S148.
Vascular endothelium plays a key role in blood pressure regulation. Recently, it has been shown that a 5% increase of plasma sodium concentration (sodium excess) stiffens endothelial cells by about 25%, leading to cellular dysfunction. Surface measurements demonstrated that the endothelial glycocalyx (eGC), an anionic biopolymer, deteriorates when sodium is elevated. In view of these results, a two-barrier model for sodium exiting the circulation across the endothelium is suggested. The first sodium barrier is the eGC which selectively buffers sodium ions with its negatively charged prote-oglycans.The second sodium barrier is the endothelial plasma membrane which contains sodium channels. Sodium excess, in the presence of aldosterone, leads to eGC break-down and, in parallel, to an up-regulation of plasma membrane sodium channels. The following hypothesis is postulated: Sodium excess increases vascular sodium permeability. Under such con-ditions (e.g. high-sodium diet), day-by-day ingested sodium, instead of being readily buffered by the eGC and then rapidly excreted by the kidneys, is distributed in the whole body before being finally excreted. Gradually, the sodium overload damages the organism.
PMCID: PMC3470790  PMID: 22471931
Aldosterone; atomic force microscopy; endothelial dysfunction; endothelial glycocalyx; epithelial sodium channel; hypertension; mechanical stiffness; salt intake; spironolactone; stiff endothelial cell syndrome

Results 1-10 (10)