Following adhesion on brain microvasculature, Neisseria meningitidis is able to cross the blood-brain barrier (BBB) by recruiting the polarity complex and the cell junction proteins, thus allowing the opening of the paracellular route. This feature is the consequence of the activation by the type IV pili of the β2-adrenergic receptor/β-arrestin signaling pathway. Here, we have extended this observation to primary peripheral endothelial cells, and we report that the interaction of N. meningitidis with the epithelium is strikingly different. The recruitment of the junctional components by N. meningitidis is indeed restricted to endothelial cell lines, and no alteration of the cell-cell junctions can be seen in epithelial monolayers following meningococcal type IV pilus-mediated colonization. Consistently, the β2-adrenergic receptor/β-arrestin pathway was not hijacked by bacteria adhering on epithelial cells. In addition, we showed that the consequences of the bacterial signaling on epithelial cells is different from that of endothelial cells, since N. meningitidis-induced signaling which protects the microcolonies from shear stress on endothelial cells is unable to do so on epithelial cells. Finally, we report that the minor pilin PilV, which has been shown to be essential for endothelial cell response, is not a required bacterial determinant to induce an epithelial cell response. These data demonstrate that even though pilus-mediated signaling induces an apparently similar cortical plaque, in epithelial and endothelial cell lineages, the signaling pathways are strikingly different in both models.