Abstract
AbstractVascular endothelial growth factor (VEGF) appears to be an important mediator of pathologic retinal angiogenesis. In understanding the mechanisms of pathologic retinal neovascularization, we found that VEGF activates PLD1 in human retinal microvascular endothelial cells, and this event is dependent on Src. In addition, VEGF activates protein kinase C-γ (PKCγ) via Src-dependent PLD1 stimulation. Inhibition of Src, PLD1, or PKCγ via pharmacologic, dominant negative mutant, or siRNA approaches significantly attenuated VEGF-induced human retinal microvascular endothelial cell migration, proliferation, and tube formation. Hypoxia also induced Src-PLD1-PKCγ signaling in retina, leading to retinal neovascularization. Furthermore, siRNA-mediated down-regulation of VEGF inhibited hypoxia-induced Src-PLD1-PKCγ activation and neovascularization. Blockade of Src-PLD1-PKCγ signaling via the siRNA approach also suppressed hypoxia-induced retinal neovascularization. Thus, these observations demonstrate, for the first time, that Src-dependent PLD1-PKCγ activation plays an important role in pathologic retinal angiogenesis.
Highlights
Introduction bition ofSrc, PLD1, or protein kinase C (PKC)␥ via pharmacologic, dominant negative mutant, or siRNA approaches significantly attenuated vascular endothelial growth factor (VEGF)-induced human retinal microvascular endothelial cell migration, proliferation, and tube formation
VEGF binds to its receptors VEGFR1/2 and stimulates a variety of signaling events leading to angiogenesis.[7,8,9,10]
With regard to downstream signaling events of VEGFRs, phospholipase C-␥–dependent mitogenactivated protein kinase activation and phosphoinositide-3 kinaseAkt-mTOR–dependent S6K1 stimulation have been shown to be involved in VEGF-induced angiogenesis.[16,17]
Summary
PLD1, or PKC␥ via pharmacologic, dominant negative mutant, or siRNA approaches significantly attenuated VEGF-induced human retinal microvascular endothelial cell migration, proliferation, and tube formation. Hypoxia induced Src-PLD1-PKC␥ signaling in retina, leading to retinal neovascularization. SiRNA-mediated downregulation of VEGF inhibited hypoxiainduced Src-PLD1-PKC␥ activation and neovascularization. Blockade of SrcPLD1-PKC␥ signaling via the siRNA approach suppressed hypoxia-induced retinal neovascularization. These observations demonstrate, for the first time, that Src-dependent PLD1-PKC␥ activation plays an important role in pathologic retinal angiogenesis. Activation of Src-PLD1-PKC␥ signaling is required for VEGF-induced human retinal microvascular endothelial cell (HRMVEC) migration, proliferation, and tube formation. Enough, activation of Src-PLD1-PKC␥ signaling is needed for hypoxia-induced VEGFmediated pathologic retinal neovascularization
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