In the past, it was believed that the expression of the epithelial sodium channel (ENaC) was restricted to epithelial tissues, such as the distal nephron, airway, sweat glands, and colon, where it is critical for sodium homeostasis. Over the past two decades, this paradigm has shifted due to the finding that ENaC is also expressed in various nonepithelial tissues, notably in vascular endothelial cells. In this review, the recent findings of the expression, regulation, and function of the endothelial ENaC (EnNaC) are discussed. The expression of EnNaC subunits is reported in a variety of endothelial cell lines and vasculatures, but this is controversial across different species and vessels and is not a universal finding in all vascular beds. The expression density of EnNaC is very faint compared to ENaC in the epithelium. To date, little is known about the regulatory mechanism of EnNaC. Through it can be regulated by aldosterone, the detailed downstream signaling remains elusive. EnNaC responds to increased extracellular sodium with the feedforward activation mechanism, which is quite different from the Na+ self-inhibition mechanism of ENaC. Functionally, EnNaC was shown to be a determinant of cellular mechanics and vascular tone as it can sense shear stress, and its activation or insertion into plasma membrane causes endothelial stiffness and reduced nitric oxide production. However, in some blood vessels, EnNaC is essential for maintaining the integrity of endothelial barrier function. In this context, we discuss the possible reasons for the distinct role of EnNaC in vasculatures.
Keywords: EnNaC; aldosterone; endothelial barrier; nitric oxide; shear stress; stiff endothelial cell syndrome.
© 2021 Wiley Periodicals LLC.