Liddle's syndrome, an inherited form of severe hypertension, is caused by mutation of the epithelial sodium channel (ENaC), developing a constitutively hyperactive form. As ENaC determines the rate of sodium reabsorption in the kidney, it was concluded that gain-of-function of the channel leads to excessive NaCl retention, resulting in vascular volume expansion and concomitant increase in blood pressure. The presence of ENaC in the endothelium, however, has been neglected in this context. Aldosterone, a mineralocorticoid hormone, also induces expression of ENaC in vascular endothelial cells, which correlates with increased cell stiffening, eventually leading to high blood pressure. As most patients afflicted with Liddle's syndrome actually do not seem volume expanded and considering the prominent effects of ENaC in the endothelium, the pathology of Liddle's syndrome needs revaluation. To this end we show that ENaC is functionally overexpressed by 33% in aortic endothelial cells of mice suffering from Liddle's syndrome compared to wild-type cells. We then determined the mechanical stiffness of these cells in comparison with wild-type and ENaC knock-out preparations using atomic force microscopy. Here we detected a rise in endothelial stiffness by 18% in case of high ENaC abundance and a drop in stiffness by 19% in ENaC knock-out cells. These findings are complemented by data obtained from in vitro models displaying up- and down-regulated ENaC levels. We therefore conclude that ENaC is involved in the pathology of Liddle's syndrome by determining endothelial stiffness and thus participating in blood pressure control.