title: 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.
authors: Departments of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
authors: Y
authors: Y
authors: Gu
authors: L J
authors: LJ
authors: Groome
authors: J S
authors: JS
authors: Alexander
authors: Y
authors: Y
authors: Wang
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D053818:Chymases / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism; D005260:Female; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000819:agonists / Q000502:physiology*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D053818:Chymases; D017077:Culture Media, Conditioned; D009842:Oligopeptides; D034741:RNA, Small Interfering; D044464:Receptor, PAR-2; D000099152:Cadherin 5; C515807:seryl-leucyl-isoleucyl-glycyl-lysyl-valinamide