Activation of proteinase-activated receptor 2 stimulates soluble vascular endothelial growth factor receptor 1 release via epidermal growth factor receptor transactivation in endothelial cells

Bahjat Al-Ani, Peter W. Hewett, Melissa J. Cudmore, Takeshi Fujisawa, Mahmoud Saifeddine, Hannah Williams, Wenda Ramma, Samir Sissaoui, Padma-Sheela Jayaraman, Motoi Ohba, Shakil Ahmad, Morley D. Hollenberg, Asif Ahmed

Research output: Contribution to journalArticle

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-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-ß1 and protein kinase C-e, 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.
Original languageEnglish
Pages (from-to)689-697
Number of pages9
JournalHypertension
Volume55
Issue number3
DOIs
Publication statusPublished - Mar 2010

Keywords

  • PAR-2
  • sVEGFR-1/sFlt-1
  • endothelium
  • factor Xa
  • HO-1
  • preeclampsia

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    Al-Ani, B., Hewett, P. W., Cudmore, M. J., Fujisawa, T., Saifeddine, M., Williams, H., Ramma, W., Sissaoui, S., Jayaraman, P-S., Ohba, M., Ahmad, S., Hollenberg, M. D., & Ahmed, A. (2010). Activation of proteinase-activated receptor 2 stimulates soluble vascular endothelial growth factor receptor 1 release via epidermal growth factor receptor transactivation in endothelial cells. Hypertension, 55(3), 689-697. https://doi.org/10.1161/HYPERTENSIONAHA.109.136333