Placenta Growth Factor-1 Exerts Time-Dependent Stabilization of Adherens Junctions Following VEGF-Induced Vascular Permeability

Jun Cai,Michael E Boulton,Lin Wu,Sergio Caballero,Asif Ahmed,David Antonetti,Stanley A Vinores,Maria B Grant,Lynn Shaw,Wen G Jiang,Sergio Li Calzi,Xiaoping Qi

doi:10.1371/journal.pone.0018076

Abstract

Increased vascular permeability is an early event characteristic of tissue ischemia and angiogenesis. Although VEGF family members are potent promoters of endothelial permeability the role of placental growth factor (PlGF) is hotly debated. Here we investigated PlGF isoforms 1 and 2 and present in vitro and in vivo evidence that PlGF-1, but not PlGF-2, can inhibit VEGF-induced permeability but only during a critical window post-VEGF exposure. PlGF-1 promotes VE-cadherin expression via the trans-activating Sp1 and Sp3 interaction with the VE-cadherin promoter and subsequently stabilizes transendothelial junctions, but only after activation of endothelial cells by VEGF. PlGF-1 regulates vascular permeability associated with the rapid localization of VE-cadherin to the plasma membrane and dephosphorylation of tyrosine residues that precedes changes observed in claudin 5 tyrosine phosphorylation and membrane localization. The critical window during which PlGF-1 exerts its effect on VEGF-induced permeability highlights the importance of the translational significance of this work in that PLGF-1 likely serves as an endogenous anti-permeability factor whose effectiveness is limited to a precise time point following vascular injury. Clinical approaches that would pattern nature's approach would thus limit treatments to precise intervals following injury and bring attention to use of agents only during therapeutic windows.

Highlights

Increased vascular permeability is an inciting event in numerous human vascular pathologies such as ischemic stroke, diabetic complications, tumorogenesis and rheumatoid arthritis [1,2,3]
Given the controversy regarding the effect of placental growth factor (PlGF) on vascular permeability we first asked whether there was a temporal dependence of the effect of PlGF on VEGF-induced vascular permeability and if this was isoform dependent
We have identified a critical window during which hPlGF-1 can inhibit VEGF-induced permeability (Fig. 1a)

Summary

Introduction

Increased vascular permeability is an inciting event in numerous human vascular pathologies such as ischemic stroke, diabetic complications, tumorogenesis and rheumatoid arthritis [1,2,3]. Intercellular junctions between endothelial cells control vascular permeability and integrity. This barrier function requires the expression and organization of VE-cadherin and claudin-5, which are essential components of adherens junctions (AJs) and tight junctions (TJs) respectively [1,4] in the blood-brain and bloodretinal barriers. As opposed to epithelial cells where the AJs and TJs can clearly be distinguished by ultrastructural analysis, in endothelial cells of the blood-brain and blood retinal barrier these junctional complexes are intermingled [1,7]. Cells require AJ formation to build TJs [6,8] and recent reports indicate that coordinated disruption of VE-cadherin intracellular interactions culminates in the restructuring of both AJs and TJs and the subsequent opening of endothelial cell-cell junctions [1,4,7]

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Results

Conclusion