There is increasing evidence that the acute-phase reactant CRP (C-reactive protein) is not only a passive marker protein for systemic inflammation but also affects the vascular system. CRP, thus is an independent risk factor for atherosclerosis and the development of hypertension. Another crucial player in atherosclerotic processes is the mineralocorticoid hormone aldosterone. Even in low physiological concentrations it triggers the expression and membrane insertion of the epithelial sodium channel (ENaC) in endothelial cells. This stimulates the development of the Stiff Endothelial Cell Syndrome (SECS) leading to reduced nitric oxide release and endothelial dysfunction. Here the hypothesis was tested that the synergy of CRP and aldosterone is an enhancer of this mechanism. By using an atomic force micoscope as a nanosensor we found that CRP and aldosterone stiffen the cells. With Quantum Dot surface labeling of ENaC we detected that CRP enhances the insertion of ENaC into the plasma membrane. In parallel, the endothelial permeability was decreased. CRP actions were prevented either by the inhibition of the intracellular aldosterone receptors using spironolactone or by the inactivation of ENaC using the specific blocker amiloride. In contrast, inhibition of the release of the vasodilating gas nitric oxide (NO) via blockade of the phosphoinositide 3-kinase/Akt pathway had no effect on the CRP-induced stiffening of endothelial cells.The data indicate that CRP enhances the effects of aldosterone on the mechanical properties of the endothelium. Thus CRP could counteract any decrease in arterial blood pressure that accompanies severe acute inflammatory processes.