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

Fingerprint

PAR-2 Receptor
Vascular Endothelial Growth Factor Receptor-1
Epidermal Growth Factor Receptor
Transcriptional Activation
Endothelial Cells
Pre-Eclampsia
Heme Oxygenase-1
Human Umbilical Vein Endothelial Cells
Mothers
Factor Xa
Simvastatin
Serine Proteases
Blood Coagulation
Carbon Monoxide
Mitogen-Activated Protein Kinases
Protein Kinase C
Small Interfering RNA
Blood Vessels
Up-Regulation
Cytokines

Keywords

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

Cite this

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. / Activation of proteinase-activated receptor 2 stimulates soluble vascular endothelial growth factor receptor 1 release via epidermal growth factor receptor transactivation in endothelial cells. In: Hypertension. 2010 ; Vol. 55, No. 3. pp. 689-697.
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Activation of proteinase-activated receptor 2 stimulates soluble vascular endothelial growth factor receptor 1 release via epidermal growth factor receptor transactivation in endothelial cells. / 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.

In: Hypertension, Vol. 55, No. 3, 03.2010, p. 689-697.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Activation of proteinase-activated receptor 2 stimulates soluble vascular endothelial growth factor receptor 1 release via epidermal growth factor receptor transactivation in endothelial cells

AU - Al-Ani, Bahjat

AU - Hewett, Peter W.

AU - Cudmore, Melissa J.

AU - Fujisawa, Takeshi

AU - Saifeddine, Mahmoud

AU - Williams, Hannah

AU - Ramma, Wenda

AU - Sissaoui, Samir

AU - Jayaraman, Padma-Sheela

AU - Ohba, Motoi

AU - Ahmad, Shakil

AU - Hollenberg, Morley D.

AU - Ahmed, Asif

PY - 2010/3

Y1 - 2010/3

N2 - 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.

AB - 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.

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KW - sVEGFR-1/sFlt-1

KW - endothelium

KW - factor Xa

KW - HO-1

KW - preeclampsia

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