Peptido-leukotrienes are potent agonists of von Willebrand factor secretion and P-selectin surface expression in human umbilical vein endothelial cells

Yvonne H. Datta, Mario Romano, Brian C. Jacobson, David E. Golan, Charles N. Serhan, Bruce M. Ewenstein

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

Background: The peptido-leukotrienes (LTs) and lipoxins (LX) are produced by platelets through the transcellular conversion of leukocyte-derived LTA4 at sites of vascular inflammation and injury, such as during coronary artery balloon angioplasty. We studied the actions of these eicosanoids on vascular endothelium. Methods and Results: We found that stimulation of cultured human umbilical vein endothelial cells (EC) with LTC4 and LTD4 resulted in the release of high-molecular-weight multimers of von Willebrand factor (vWF) in a concentration- and time-dependent fashion, as measured by ELISA. Neither LXA4 nor LXB4 stimulated vWF release. LTC4 and LTD4 also stimulated a rapid increase in the surface expression of P-selectin indicated by decreased binding of anti-P-selectin monoclonal antibody-coated beads. Fluorescence cytometry detected prolonged peaks of [Ca2+](i) in EC in response to concentrations of thrombin and LTD4 that induce near-maximal vWF secretion. In contrast, concentrations of LTC4 that induce similar levels of vWF secretion produced only asynchronous oscillations of [Ca2+](i) in most EC and rarely induced prolonged peaks of [Ca2+](i). Depletion of external Ca2+ had no apparent impact on LT-stimulated [Ca2+](i) transients and vWF secretion, implicating an intracellular pool as the source of this response. Staurosporine, sphingosine, and H-7 each had only modest effects in peptido- LT-induced vWF secretion, suggesting that protein kinase C is not a primary mediator of peptido-LT-induced exocytosis. Inhibitors of cyclooxygenase and platelet-activating factor had no effect on peptido-LT-mediated vWF secretion. Conclusions: Through the induction of vWF secretion and P-selectin surface expression, peptido-LTs are likely to play an important role in the interrelated processes of hemostasis and inflammation.

Original languageEnglish (US)
Pages (from-to)3304-3311
Number of pages8
JournalCirculation
Volume92
Issue number11
DOIs
StatePublished - Dec 1 1995

Keywords

  • eicosanoid
  • leukotriene
  • secretion
  • transcellular metabolism
  • von Willebrand factor

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