Antagonism of VEGF-A-induced increase in vascular permeability by an integrin α3β1-Shp-1-cAMP/PKA pathway.

ABSTRACT: In cancer, VEGF-induced increase in vascular permeability results in increased interstitial pressure, reducing perfusion and increasing hypoxia, which reduce delivery of chemotherapeutic agents and increase resistance to ionizing radiation. Here, we show that both TIMP-2 and Ala + TIMP-2, a TIMP-2 mutant without matrix metalloproteinase inhibitory activity, antagonize the VEGF-A-induced increase in vascular permeability, both in vitro and in vivo. Like other agents known to preserve endothelial barrier function, TIMP-2 elevates cytosolic levels of cAMP and increases cytoskeletal-associated vascular endothelial cadherin in human microvascular endothelial cells. All of these effects are completely ablated by selective knockdown of integrin α3β1 expression, expression of a dominant negative p

SUBMITTER: Kim SH 

PROVIDER: S-EPMC3520626 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature