The mineralocorticoid hormone aldosterone has been shown to concomitantly increase the surface abundance of the epithelial Na⁺ channel (ENaC) and stiffness of the cell cortex in vascular endothelial cells. The latter entails reduced release of the vasodilator nitric oxide (endothelial dysfunction), thus evoking vasoconstriction and increase in vascular tone and blood pressure. We therefore hypothesize that ENaC in the vascular endothelium is itself pivotal for the regulation of endothelial (and thus vascular) function.

To explore the effects of ENaC surface abundance on the cortical stiffness of vascular endothelial cells we employedin vitro andex vivo models with genetically altered ENaC abundance: Endothelial cell lines with stable knockdown and high-level expression of aENaC andin situ endothelial cells ofex vivo aorta preparations from mice models for Liddle's syndrome, an inherited form of hypertension caused by gain-of-function-mutations in ENaC.

Using quantum dot mediated single aENaC staining and atomic force microscopy we have found that low levels of aENaC in endothelial cells evoked reduced cortical stiffness, whereas increased aENaC expression induced elevated cortical stiffness. By employingex vivopreparations from a mouse model for Liddle's syndrome, we furthermore show that this disorder evokes enhanced ENaC expression and increased cortical stiffness in vascular endothelial cells.

We conclude that ENaC (dys)function determines cortical endothelial stiffness and thus contributes to the pathology of Liddle's syndrome, and potentially the control of vascular tone. Following these findings, it will be interesting to determine the effect of aldosterone synthase (Cyp11b2) knockout (mouse model) on endothelial function.