title: Activation of proteinase-activated receptor 2 stimulates soluble vascular endothelial growth factor receptor 1 release via epidermal growth factor receptor transactivation in endothelial cells.
abstract: The proteinase-activated receptor 2 (PAR-2) expression is increased in endothelial cells derived from women with preeclampsia, characterized by widespread maternal endothelial damage, which occurs as a consequence of elevated soluble vascular endothelial growth factor receptor-1 (sVEGFR-1; commonly known as sFlt-1) in the maternal circulation. Because PAR-2 is upregulated by proinflammatory cytokines and activated by blood coagulation serine proteinases, we investigated whether activation of PAR-2 contributed to sVEGFR-1 release. PAR-2-activating peptides (SLIGRL-NH(2) and 2-furoyl-LIGRLO-NH(2)) and factor Xa increased the expression and release of sVEGFR-1 from human umbilical vein endothelial cells. Enzyme-specific, dominant-negative mutants and small interfering RNA were used to demonstrate that PAR-2-mediated sVEGFR-1 release depended on protein kinase C-beta(1) and protein kinase C-epsilon, which required intracellular transactivation of epidermal growth factor receptor 1, leading to mitogen-activated protein kinase activation. Overexpression of heme oxygenase 1 and its gaseous product, carbon monoxide, decreased PAR-2-stimulated sVEGFR-1 release from human umbilical vein endothelial cells. Simvastatin, which upregulates heme oxygenase 1, also suppressed PAR-2-mediated sVEGFR-1 release. These results show that endothelial PAR-2 activation leading to increased sVEGFR-1 release may contribute to the maternal vascular dysfunction observed in preeclampsia and highlights the PAR-2 pathway as a potential therapeutic target for the treatment of preeclampsia.
authors.affiliation: Department of Reproductive and Vascular Biology, Institute for Biomedical Research, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Bahjat
authors.initials: B
authors.lastname: Al-Ani
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hewett
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Cudmore
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Saifeddine
authors.forename: Hannah
authors.initials: H
authors.lastname: Williams
authors.forename: Wenda
authors.initials: W
authors.lastname: Ramma
authors.forename: Samir
authors.initials: S
authors.lastname: Sissaoui
authors.forename: Padma-Sheela
authors.initials: PS
authors.lastname: Jayaraman
authors.forename: Motoi
authors.initials: M
authors.lastname: Ohba
authors.forename: Shakil
authors.initials: S
authors.lastname: Ahmad
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
mesh_terms: D002248:Carbon Monoxide / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D015951:Factor Xa / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000819:agonists / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology; D012995:Solubility; D014471:Umbilical Veins / Q000166:cytology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D044464:Receptor, PAR-2; D002248:Carbon Monoxide; D019821:Simvastatin; D051547:Heme Oxygenase-1; D066246:ErbB Receptors; D040281:Vascular Endothelial Growth Factor Receptor-1; D016392:Proto-Oncogene Proteins pp60(c-src); D011493:Protein Kinase C; D015951:Factor Xa