Endothelial cells form the inner layer of blood vessels and are exposed to the hemodynamic traction forces of the streaming blood (e.g. laminar shear stress). This ‘strategic position’ enables the endothelium to control vascular function. Blood flow mediated shear stress rhythmically acts on and deforms endothelial cells at their very surface and thus controls endothelial nitric oxide synthase (eNOS) activity. After synthesis and release, NO diffuses to adjacent vascular smooth muscle cells where it triggers vasodilation via a cGMP-dependent pathway. During the last years it became clear to us that the nanomechanical properties of endothelial cells (i.e. cortical stiffness) and NO release are tightly coupled. A soft endothelial cell cortex is easily deformable by the streaming blood so that NO release by soft endothelial cells is higher than that of endothelial cells with a stiff cell cortex. Cell softening is found also enhanced by extracellular potassium and/or cell depolarization. In contrast, cell stiffness and reduced NO release are triggered by high physiological plasma sodium concentrations (> 140 mM). A reduced bioavailability of NO in the vessel wall leads to impaired vasodilation, a hallmark of endothelial dysfunction, also termed ‘stiff endothelial cell syndrome’ (SECS). Thus, the degree of endothelial stiffness serves as a critical parameter in the regulation of vascular function as it regulates cellular responses to biochemical and biophysical signals. The physiological state of the endothelium thereby depends on the mechanical stiffness of endothelial cells. Recently, we could show that the endothelial Na+ channel (EnNaC) is a crucial regulator of endothelial stiffness as its membrane abundance stiffens the cortex.
Model of EnNaC-dependent transition from endothelial function to dysfunction.
Normally, the endothelial cell is protected by a well-developed glycocalyx and EnNaC membrane expression is low. Thus, the access of Na+ into the endothelial cell is limited, NO is released and vasodilation is maintained. Increased EnNaC membrane abundance together with deranged glycocalyx facilitate Na+ entry into endothelial cells and triggers the polymerization of G-actin to F-actin. As a result, the endothelial cortex stiffens and NO release is reduced leading to SECS and endothelial dysfunction.
(After Warnock, Kusche-Vihrog et al., Nat. Rev. Nephrol., 2014)
The group is supported by the expert technical assistance of Marianne Wilhelmi
In general my group is interested in mechanisms underlying the regulation of endothelial nanomechanics. We are interested in the following topics:
- EnNaC and endothelial (dys)function
- Endothelial nanomechanics as a link to arterial stiffness and cardiovascular pathologies
- Sodium and inflammatory processes of the vascular endothelium
- The endothelial glycocalyx as important barrier structure