Rap1B promotes VEGF-induced endothelial permeability and is required for dynamic regulation of the endothelial barrier. J Cell Sci 2018 Jan 10;131(1)
Date
12/10/2017Pubmed ID
29222111Pubmed Central ID
PMC5818062DOI
10.1242/jcs.207605Scopus ID
2-s2.0-85045634293 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
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.
Author List
Lakshmikanthan S, Sobczak M, Li Calzi S, Shaw L, Grant MB, Chrzanowska-Wodnicka MAuthor
Magdalena Chrzanowska PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCapillary Permeability
Cell Adhesion
Cell Line
Diabetes Mellitus, Experimental
Endothelium, Vascular
Female
Humans
Intercellular Junctions
Male
Mice
Mice, Knockout
Neovascularization, Physiologic
Signal Transduction
Vascular Endothelial Growth Factor A
rap GTP-Binding Proteins
