An Inhibitory Role of the Phosphatidylinositol 3-Kinase-signaling Pathway in Vascular Endothelial Growth Factor-induced Tissue Factor Expression

Sabine Blum, Katja Issbrüker, Antje Willuweit, Stephanie Hehlgans, Markus Lucerna, Diana Mechtcheriakova, Kenneth Walsh, Dietmar Von der Ahe, Erhard Hofer, Matthias Clauss

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Vascular endothelial growth factor (VEGF) is not only essential for vasculogenesis and angiogenesis but is also capable of inducing tissue factor, the prime initiator of coagulation, in endothelial cells. In this study we have analyzed the VEGF-elicited pathways involved in the induction of tissue factor in human umbilical cord vein endothelial cells. Using specific low molecular weight inhibitors we could demonstrate a crucial role of the p38 and Erk-1/2 mitogen-activated protein (MAP) kinases. In contrast, treatment with wortmannin or LY294002, inhibitors of phosphatidylinositol 3 (PI3)-kinase, resulted in a strong enhancement of the VEGF-induced tissue factor production, indicating a negative regulatory role of the PI3-kinase on tissue factor-inducing pathways. Accordingly, transduction with constitutively active Akt led to a reduction of VEGF-induced tissue factor production. Western blot analyses using antibodies specific for phosphorylated p38 showed an enhanced activation of this MAP kinase in human umbilical cord vein endothelial cells when stimulated with VEGF in the presence of wortmannin in comparison to either agent alone. Thus, the negative regulation of the PI3-kinase pathway on endothelial tissue factor activity can be explained at least in part by a suppression of this MAP kinase-signaling pathway. This is the first demonstration of a reciprocal relationship between procoagulant activity and the PI3-kinase-Akt signaling pathway, and it reveals a novel mechanism by which tissue factor expression can be controlled in endothelial cells.

Original languageEnglish (US)
Pages (from-to)33428-33434
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number36
DOIs
StatePublished - Sep 7 2001
Externally publishedYes

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Phosphatidylinositol 3-Kinase
Thromboplastin
Vascular Endothelial Growth Factor A
Endothelial cells
Umbilical Cord
Human Umbilical Vein Endothelial Cells
Mitogen-Activated Protein Kinases
Endothelial Cells
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Mitogen-Activated Protein Kinase 1
Coagulation
Endothelium
Demonstrations
Molecular Weight
Western Blotting
Chemical activation
Molecular weight
Antibodies

ASJC Scopus subject areas

  • Biochemistry

Cite this

An Inhibitory Role of the Phosphatidylinositol 3-Kinase-signaling Pathway in Vascular Endothelial Growth Factor-induced Tissue Factor Expression. / Blum, Sabine; Issbrüker, Katja; Willuweit, Antje; Hehlgans, Stephanie; Lucerna, Markus; Mechtcheriakova, Diana; Walsh, Kenneth; Von der Ahe, Dietmar; Hofer, Erhard; Clauss, Matthias.

In: Journal of Biological Chemistry, Vol. 276, No. 36, 07.09.2001, p. 33428-33434.

Research output: Contribution to journalArticle

Blum, S, Issbrüker, K, Willuweit, A, Hehlgans, S, Lucerna, M, Mechtcheriakova, D, Walsh, K, Von der Ahe, D, Hofer, E & Clauss, M 2001, 'An Inhibitory Role of the Phosphatidylinositol 3-Kinase-signaling Pathway in Vascular Endothelial Growth Factor-induced Tissue Factor Expression', Journal of Biological Chemistry, vol. 276, no. 36, pp. 33428-33434. https://doi.org/10.1074/jbc.M105474200
Blum, Sabine ; Issbrüker, Katja ; Willuweit, Antje ; Hehlgans, Stephanie ; Lucerna, Markus ; Mechtcheriakova, Diana ; Walsh, Kenneth ; Von der Ahe, Dietmar ; Hofer, Erhard ; Clauss, Matthias. / An Inhibitory Role of the Phosphatidylinositol 3-Kinase-signaling Pathway in Vascular Endothelial Growth Factor-induced Tissue Factor Expression. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 36. pp. 33428-33434.
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