StxB induces WPB exocytosis in a PLD1-dependent manner. Stx1B increases intracellular Ca2+ and activates PKCα, RalA, Arf6, and to a lesser extent, RhoA. In contrast, Stx2B does not affect PKCα and Ca2+ signaling but activates RalA, Arf6, and RhoA. All of these pathways can contribute to the activation of PLD1, which leads to WPB exocytosis and VWF secretion. Stx2B is a relatively potent activator of RhoA and therefore has a more pronounced effect on actin cytoskeleton remodeling and endothelial monolayer permeability.