In:
Journal of Cell Science, The Company of Biologists
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 hyper-permeability. We demonstrated 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 Rap1's 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 of 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.
Type of Medium:
Online Resource
ISSN:
1477-9137
,
0021-9533
Language:
English
Publisher:
The Company of Biologists
Publication Date:
2017
detail.hit.zdb_id:
219171-4
detail.hit.zdb_id:
1483099-1
SSG:
12
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