Rap1B promotes VEGF-induced endothelial permeability and is required for dynamic regulation of the endothelial barrier

ABSTRACT Vascular endothelial growth factor (VEGF), a key angiogenic and permeability factor, plays an important role in new blood vessel formation. However, abnormal VEGF-induced VEGFR2 signaling leads to hyperpermeability. We have shown previously that Rap1, best known for promoting cell adhesion and vessel stability, is a critical regulator of VEGFR2-mediated angiogenic and shear-stress EC responses. To determine the role of Rap1 role in endothelial barrier dynamics, we examined vascular permeability in EC-specific Rap1A- and Rap1B-knockout mice, cell–cell junction remodeling and EC monolayer resistivity in Rap1-deficient ECs under basal, inflammatory or elevated VEGF conditions. Deletion of either Rap1 isoform impaired de novo adherens junction (AJ) formation and recovery from LPS-induced barrier disruption in vivo . However, only Rap1A deficiency increased permeability in ECs and lung vessels. Interestingly, Rap1B deficiency attenuated VEGF-induced permeability in vivo and AJ remodeling in vitro . Therefore, only Rap1A is required for the maintenance of normal vascular integrity. Importantly, Rap1B is the primary isoform essential for normal VEGF-induced EC barrier dissolution. Deletion of either Rap1 isoform protected against hyper permeability in the STZ-induced diabetes model, suggesting clinical implications for targeting Rap1 in pathologies with VEGF-induced hyperpermeability.