Abstract
High dietary salt (NaCl) is a known risk factor for cardiovascular pathologies and inflammation. High plasma Na+ concentrations (high Na+) have been shown to stiffen the endothelial cortex and decrease nitric oxide (NO) release, a hallmark of endothelial dysfunction. Here we report that chronic high Na+ damages the endothelial glycocalyx (eGC), induces release of inflammatory cytokines from the endothelium and promotes monocyte adhesion. Single cell force spectroscopy reveals that high Na+ enhances vascular adhesion protein-1 (VCAM-1)-dependent adhesion forces between monocytes and endothelial surface, giving rise to increased numbers of adherent monocytes on the endothelial surface. Mineralocorticoid receptor antagonism with spironolactone prevents high Na+-induced eGC deterioration, decreases monocyte-endothelium interactions, and restores endothelial function, indicated by increased release of NO. Whereas high Na+ decreases NO release, it induces endothelial release of the pro-inflammatory cytokines IL-1ß and TNFα. However, in contrast to chronic salt load (hours), in vivo and in vitro, an acute salt challenge (minutes) does not impair eGC function. This study identifies the eGC as important mediator of inflammatory processes and might further explain how dietary salt contributes to endothelialitis and cardiovascular pathologies by linking endothelial nanomechanics with vascular inflammation.
Highlights
High salt (NaCl) intake is increasingly considered a risk factor for inflammatory pathologies and for the development of autoimmune diseases[1,2,3,4,5]
Monocyte adhesion is the first step towards vascular inflammation[19] and it is postulated that high salt has pro-inflammatory properties[3,20]
Since mechanical stiffening of endothelial cells strongly contributes to impaired nitric oxide (NO) release[27], we propose that Na+-induced modifications of the physical properties of the outer layer of endothelial cells are early events of endothelial dysfunction which may culminate in chronic inflammatory diseases
Summary
High salt (NaCl) intake is increasingly considered a risk factor for inflammatory pathologies and for the development of autoimmune diseases[1,2,3,4,5]. Using the atomic force microscope (AFM) tip as a nanosensor it could be demonstrated that, in the presence of aldosterone, a small rise in extracellular Na+ concentration by only 7% (from 137 to 147 mM Na+) significantly increases the stiffness of the endothelial cortex, an actin-rich layer 50–200 nm beneath the plasma membrane[6]. Under these conditions, release of the vasodilator nitric oxide (NO) from endothelial cells was found to be significantly reduced[6], indicating salt-induced transition towards endothelial dysfunction. Our data indicate that high Na+ impairs the integrity of the lumen-eGC interface and promotes vascular inflammation, providing a promising target for therapeutic intervention
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