ARHGEF18 is a flow-responsive 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. When phosphorylated, ARHGEF18 interacts with tight junctions; participates in EC elongation, alignment, and migration; and allows the maintenance of the endothelial barrier under physiological flow conditions. In mice, ARHGEF18 is involved in tight junction formation, flow response of ECs, and the control of vascular permeability. 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.