Activation of cytosolic phospholipase A2-α as a novel mechanism regulating endothelial cell cycle progression and angiogenesis

Shane P. Herbert, Adam F. Odell, Sreenivasan Ponnambalam, John H. Walker

    Research output: Contribution to journalArticlepeer-review


    Release of endothelial cells from contact-inhibition and cell cycle re-entry is required for the induction of new blood vessel formation by angiogenesis. Using a combination of chemical inhibition, loss of function, and gain of function approaches, we demonstrate that endothelial cell cycle re-entry, S phase progression, and subsequent angiogenic tubule formation are dependent upon the activity of cytosolic phospholipase A2-α (cPLA2α). Inhibition of cPLA2α activity and small interfering RNA (siRNA)-mediated knockdown of endogenous cPLA2α reduced endothelial cell proliferation. In the absence of cPLA2α activity, endothelial cells exhibited retarded progression from G1 through S phase, displayed reduced cyclin A/cdk2 expression, and generated less arachidonic acid. In quiescent endothelial cells, cPLA2α is inactivated upon its sequestration at the Golgi apparatus. Upon the stimulation of endothelial cell proliferation, activation of cPLA2α by release from the Golgi apparatus was critical to the induction of cyclin A expression and efficient cell cycle progression. Consequently, inhibition of cPLA2α was sufficient to block angiogenic tubule formation in vitro. Furthermore, the siRNA-mediated retardation of endothelial cell cycle re-entry and proliferation was reversed upon overexpression of an siRNA-resistant form of cPLA2α. Thus, activation of cPLA2α acts as a novel mechanism for the regulation of endothelial cell cycle re-entry, cell cycle progression, and angiogenesis. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
    Original languageEnglish
    Pages (from-to)5784-5796
    Number of pages12
    JournalJournal of Biological Chemistry
    Issue number9
    Publication statusPublished - 27 Feb 2009


    • Arachidonic Acid/metabolism
    • Blotting, Western
    • Cell Cycle/*physiology
    • Cell Proliferation
    • Cells, Cultured
    • Cytosol
    • Dermis/cytology/enzymology
    • Endothelium, Vascular/*cytology
    • Enzyme Activation
    • Fibroblasts/cytology/enzymology
    • Flow Cytometry
    • Fluorescent Antibody Technique
    • Golgi Apparatus/metabolism
    • Group IV Phospholipases A2/antagonists & inhibitors/genetics/*metabolism
    • Humans
    • Immunoprecipitation
    • *Neovascularization, Physiologic
    • RNA, Small Interfering/pharmacology
    • Umbilical Veins/cytology/enzymology


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