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Scientific article
English

Protein kinase C-delta mediates von Willebrand factor secretion from endothelial cells in response to vascular endothelial growth factor (VEGF) but not histamine

Published inJournal of thrombosis and haemostasis, vol. 6, no. 11, p. 1962-1969
Publication date2008
Abstract

BACKGROUND: Vascular endothelial growth factor (VEGF) and histamine induce von Willebrand factor (VWF) release from vascular endothelial cells. Protein kinase C (PKC) is involved in the control of exocytosis in many secretory cell types. OBJECTIVES: We investigated the role of PKC and the interactions between PKC and Ca2+ signaling in both VEGF-induced and histamine-induced VWF secretion from human umbilical vein endothelial cells (HUVECs). RESULTS: Several PKC inhibitors (staurosporine, Ro31-8220, myristoylated PKC peptide inhibitor and Go6983) block VEGF-induced but not histamine-induced VWF secretion. PKC-alpha and novel PKCs (PKC-delta, PKC-epsilon, and PKC-eta), but not PKC-beta, are expressed in HUVECs. Both VEGF and histamine activate PKC-delta. However, gene inactivation experiments using small interfering RNA indicate that PKC-delta (but not PKC-alpha) is involved in the regulation of VEGF-induced but not histamine-induced secretion. Both VEGF and histamine induce a rise in cytosolic free Ca2+ ([Ca2+]c), but the response to VEGF is weaker and even absent in a significant subset of cells. Furthermore, VEGF-induced secretion is largely preserved when the rise in [Ca2+]c is prevented by BAPTA-AM. CONCLUSIONS: Our study identifies striking agonist specificities in signal-secretion coupling. Histamine-induced secretion is dependent on [Ca2+]c but not PKC, whereas VEGF-induced secretion is largely dependent on PKC-delta and significantly less on [Ca2+]c. Our data firmly establish the key role of PKC-delta in VEGF-induced VWF release, but suggest that a third, VEGF-specific, signaling intermediate is required as a PKC-delta coactivator.

Keywords
  • Calcium Signaling
  • Cells, Cultured
  • Endothelial Cells/secretion
  • Endothelium, Vascular/cytology
  • Histamine/pharmacology
  • Humans
  • Protein Kinase C-delta/metabolism
  • Vascular Endothelial Growth Factor A/pharmacology/physiology
  • Von Willebrand Factor/secretion
Citation (ISO format)
LORENZI, Olivier et al. Protein kinase C-delta mediates von Willebrand factor secretion from endothelial cells in response to vascular endothelial growth factor (VEGF) but not histamine. In: Journal of thrombosis and haemostasis, 2008, vol. 6, n° 11, p. 1962–1969. doi: 10.1111/j.1538-7836.2008.03138.x
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Article (Accepted version)
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ISSN of the journal1538-7836
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