Activation of Proteinase-Activated Receptor 2 Stimulates Soluble Vascular Endothelial Growth Factor Receptor 1 Release via Epidermal Growth Factor Receptor Transactivation in Endothelial Cells

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2010-03, Vol.55 (3), p.689-697
• Main Authors: Al-Ani, Bahjat, Hewett, Peter W, Cudmore, Melissa J, Fujisawa, Takeshi, Saifeddine, Mahmoud, Williams, Hannah, Ramma, Wenda, Sissaoui, Samir, Jayaraman, Padma-Sheela, Ohba, Motoi, Ahmad, Shakil, Hollenberg, Morley D, Ahmed, Asif
• Format: Article
• Language: English
• Subjects: Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Carbon Monoxide - metabolism; Cardiology. Vascular system; Cells, Cultured; Down-Regulation - drug effects; Down-Regulation - physiology; Endothelial Cells - cytology; Endothelial Cells - metabolism; Factor Xa - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Expression - physiology; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Kidney - cytology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Medical sciences; Pre-Eclampsia - metabolism; Pregnancy; Protein Kinase C - metabolism; Proto-Oncogene Proteins pp60(c-src) - metabolism; Receptor, Epidermal Growth Factor - metabolism; Receptor, PAR-2 - agonists; Receptor, PAR-2 - metabolism; Simvastatin - pharmacology; Solubility; Umbilical Veins - cytology; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Vertebrates: cardiovascular system
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.109.136333

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-β1 and protein kinase C- , 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.