PLD1-dependent PKCγ activation downstream to Src is essential for the development of pathologic retinal neovascularization

Qiuhua Zhang, Dong Wang, Venkatesh Kundumani-Sridharan, Laxmisilpa Gadiparthi, Dianna A. Johnson, Gabor Tigyi, Rao Gadiparthi

Research output: Contribution to journalArticle

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Abstract

Vascular 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 downregulation 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.

Original languageEnglish (US)
Pages (from-to)1377-1385
Number of pages9
JournalBlood
Volume116
Issue number8
DOIs
StatePublished - Aug 26 2010

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Pathologic Neovascularization
Retinal Neovascularization
Protein Kinase C
Vascular Endothelial Growth Factor A
Chemical activation
Small Interfering RNA
Endothelial cells
Endothelial Cells
src-Family Kinases
Cell Movement
Retina
Down-Regulation
Cell Proliferation
Hypoxia

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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PLD1-dependent PKCγ activation downstream to Src is essential for the development of pathologic retinal neovascularization. / Zhang, Qiuhua; Wang, Dong; Kundumani-Sridharan, Venkatesh; Gadiparthi, Laxmisilpa; Johnson, Dianna A.; Tigyi, Gabor; Gadiparthi, Rao.

In: Blood, Vol. 116, No. 8, 26.08.2010, p. 1377-1385.

Research output: Contribution to journalArticle

Zhang, Qiuhua ; Wang, Dong ; Kundumani-Sridharan, Venkatesh ; Gadiparthi, Laxmisilpa ; Johnson, Dianna A. ; Tigyi, Gabor ; Gadiparthi, Rao. / PLD1-dependent PKCγ activation downstream to Src is essential for the development of pathologic retinal neovascularization. In: Blood. 2010 ; Vol. 116, No. 8. pp. 1377-1385.
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abstract = "Vascular 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 downregulation 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.",
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