PAR-2 triggers placenta-derived protease-induced altered VE-cadherin reorganization at endothelial junctions in preeclampsia

Abstract

PAR-2 is a G-protein coupled protease receptor whose activation in endothelial cells (ECs) is associated with increased solute permeability. VE-cadherin is an endothelial specific junction protein, which exhibits a disorganized distribution at cell junction during inflammation and is a useful indicator of endothelial barrier dysfunction. In the present study, we tested the hypothesis that PAR-2 activation mediates placenta-derived chymotrypsin-like protease (CLP)-induced endothelial junction disturbance and permeability in preeclampsia (PE). PAR-2 and VE-cadherin were examined by immunofluorescent staining. Specific CLP-induced PAR-2 activation and altered VE-cadherin distribution was assessed following depletion of protease chymotrypsin in the placental conditioned medium and after PAR-2 siRNA. VE-cadherin assembly was determined by treating cells with protease chymotrypsin and/or the specific PAR-2 agonist SLIGKV-NH2. Our results showed: 1) placental conditioned medium not only disturbed VE-cadherin distribution at cell junctions but also activated PAR-2 in ECs; 2) PAR-2 siRNA blocked the placental conditioned medium induced PAR-2 upregulation and disorganization of VE-cadherin at cell junctions; 3) PAR-2 agonist induced PAR-2 activation and VE-cadherin reorganization were dose-dependent; and 4) PAR-2 agonist could stimulate ERK1/2 activation. These results strongly suggest that proteases produced by the placenta elicit endothelial barrier dysfunction via a PAR-2 signaling regulatory mechanism in PE.

Testisin/Prss21 deficiency causes increased vascular permeability and a hemorrhagic phenotype during luteal angiogenesis

“…altered VE-cadherin expression, and permeability changes [52][53][54] show that PAR-2 activation causes the loss of junctional VE-cadherin resulting in barrier disruption, in contrast to the observed barrier protective activity of testisin observed in the present study. Future studies are required to investigate whether PAR-2 regulation could be involved in testisin-mediated barrier protection of the microvasculature, or whether other substrates are involved.…”

PAR1&2driven placenta EVT invasion act via LRP5/6 as coreceptors

“…We also showed the association between the role of compromised PAR 1 , functional polymorphisms, and adverse pregnancy outcomes of preterm birth and repeated early pregnancy loss 42,43 . Others have shown, that PAR 2 sh RNA silencing attenuated vascular endothelial cadherin; VE‐cadherin reorganization in endothelial cell junctions, 44 the association of PAR 2 , and we have shown that birth and repeated early pregnancy loss 42 and inhibited the increased endothelial permeability and barrier dysfunction in PE.…”

The Involvement of Cell Adhesion Molecules, Tight Junctions, and Gap Junctions in Human Placentation

“…It also enhances the binding of the iEVTs to the endothelial cells [46]. During arterial remodeling, VE-cad is upregulated in the evEVTs to enhance their trans-endothelial migration and invasion [30,74,75] while failure of the EVT to upregulate VE-cad is observed in the placentae of preeclamptic women [30,76,77]. The role of VE-cad in trophoblast differentiation is not known.…”