Group VIA calcium-independent phospholipase A2 mediates endothelial cell S phase progression.
Arachidonic acid and its metabolites have been previously implicated in the regulation of endothelial cell proliferation. Arachidonic acid may be liberated from cellular phospholipids by the action of group VIA calcium-independent phospholipase A2 (iPLA2-VIA). Consequently, we tested the hypothesis that iPLA2-VIA activity is linked to the regulation of endothelial cell proliferation. Inhibition of iPLA2 activity by bromoenol lactone (BEL) was sufficient to entirely block endothelial cell growth. BEL dose-dependently inhibited endothelial cell DNA synthesis in a manner that was reversed upon the exogenous addition of arachidonic acid. DNA synthesis was inhibited by the S-isomer and not by the R-isomer of BEL, demonstrating that endothelial cell proliferation is mediated specifically by iPLA2-VIA. iPLA2-VIA activity was critical to the progression of endothelial cells through S phase and is required for the expression of the cyclin A/cdk2 complex. Thus, inhibition of iPLA2-VIA blocks S phase progression and results in exit from the cell cycle. Inhibition of iPLA2-VIA-mediated endothelial cell proliferation is sufficient to block angiogenic tubule formation in co-culture assays. Consequently, iPLA2-VIA is a novel regulator of endothelial cell S phase progression, cell cycle residence, and angiogenesis.
Herbert
Shane P
SP
Faculty of Biological Sciences, Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
Walker
John H
JH
D016718:Arachidonic Acid / Q000494:pharmacology; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D054522:Group VI Phospholipases A2; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology; D018919:Neovascularization, Physiologic; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism* / Q000502:physiology*; D054467:Phospholipases A2; D011753:Pyrones / Q000494:pharmacology; D016196:S Phase; D013997:Time Factors
D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D011753:Pyrones; D016718:Arachidonic Acid; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human; D054467:Phospholipases A2