ARHGEF18 is a flow-responding exchange factor controlling endothelial tight junctions and vascular leakage

The shear stress resulting from blood flow is a major regulator of endothelial cell (EC) biology and morphology. Rho protein-mediated cytoskeleton remodeling is an early and essential step of EC responses to flow. However, how Rho protein signaling is controlled by shear stress remains unclear. Here we demonstrate that phosphorylation, activity and expression of the Rho nucleotide exchange factor (RhoGEF) ARHGEF18 in ECs are modulated by the magnitude of shear stress. ARHGEF18 interacts with tight junctions, participates in ECs elongation and alignment and allows the maintenance of the endothelial barrier under physiological flow conditions. ARHGEF18 also promotes EC adhesion and migration by controlling focal adhesion formation. In vivo, ARHGEF18 is involved in flow response of ECs and in the control of vascular permeability in mice. Together, our results identified ARHGEF18 as the first flow-sensitive RhoGEF in ECs, whose activity is essential for the maintenance of intercellular junctions and the control of vascular permeability in vivo.