Journal
HYPERTENSION
Volume 55, Issue 3, Pages 689-U41Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.109.136333
Keywords
PAR-2; sVEGFR-1/sFlt-1; endothelium; factor Xa; HO-1; preeclampsia
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Funding
- Medical Research Council [G0601295, G0700288]
- British Heart Foundation
- Canadian Institutes of Health Research
- MRC [G0601295, G0700288] Funding Source: UKRI
- British Heart Foundation [RG/09/001/25940] Funding Source: researchfish
- Medical Research Council [G0601295, G0700288] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [22590105] Funding Source: KAKEN
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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-NH2 and 2-furoyl-LIGRLO-NH2) 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. (Hypertension. 2010; 55: 689-697.)
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