Abstract
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.
Highlights
Arachidonic acid (AA)2 and its metabolites have previously been implicated in the control of proliferation in a variety of cell types including endothelial cells [7,8,9,10,11,12]
We report that independent PLA2s (iPLA2)-VIA but not iPLA2-VIB is critical to endothelial cell proliferation, angiogenesis, and S phase progression
We define a novel role for iPLA2-VIA in the regulation of endothelial cell S phase progression and angiogenesis. iPLA2-VIA has previously been implicated in the regulation of the proliferation of a variety of cell types [33, 41,42,43,44,45,46,47]
Summary
Arachidonic acid (AA)2 and its metabolites have previously been implicated in the control of proliferation in a variety of cell types including endothelial cells [7,8,9,10,11,12]. We hypothesized that iPLA2-mediated AA release may play a central role in the regulation of endothelial cell proliferation and angiogenesis. IPLA2 Activity Mediates Endothelial Cell DNA Synthesis— The effects of BEL on HUVEC DNA synthesis was assessed by determining BrdUrd incorporation into cellular DNA in the presence of varying concentrations of BEL (Fig. 2A).
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