March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
PDCL3 Regulates Endothelial Cell Proliferation And Angiogenesis Through The Generation Of Functional VEGFR-2
Author Affiliations & Notes
  • Manisha N. Mehta
    Pathology, Boston University, Newton, Massachusetts
  • Srimathi Srinivasan
    Ophthalmology and Pathology, Boston University, Boston University, Massachusetts
  • Rosana D. Meyer
    Ophthalmology and Pathology, Boston University, Boston University, Massachusetts
  • Ricardo Lugo
    Ophthalmology and Pathology, Boston University, Boston University, Massachusetts
  • Vipul Chitalia
    Massachusetts Institute of Technology, Harvard-MIT Division of Health Science and Technology, Harvard University, Massachusetts
  • Nader Rahimi
    Ophthalmology and Pathology, Boston University, Boston University, Massachusetts
  • Footnotes
    Commercial Relationships  Manisha N. Mehta, None; Srimathi Srinivasan, None; Rosana D. Meyer, None; Ricardo Lugo, None; Vipul Chitalia, None; Nader Rahimi, None
  • Footnotes
    Support  National Institute of Health (NIH/NEI) to NR and Pathology, Boston University and Massachusetts Lions Foundation grant to Department of Ophthalmology
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 3005. doi:
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      Manisha N. Mehta, Srimathi Srinivasan, Rosana D. Meyer, Ricardo Lugo, Vipul Chitalia, Nader Rahimi; PDCL3 Regulates Endothelial Cell Proliferation And Angiogenesis Through The Generation Of Functional VEGFR-2. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3005.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Angiogenesis, a hallmark step in ocular neovascularization, is primarily driven by the function of VEGF on its receptor, VEGFR-2. Central to the initiation of angiogenesis by VEGF, the abundance of VEGFR-2 on the surface of endothelial cells is essential for VEGF to recognize and activate VEGFR-2. We have identified PDCL3 (phosducin like 3) as a novel protein involved in the stabilization of VEGFR-2 by serving as a VEGFR-2 co-chaperone protein.

Methods: : Various molecular and cell biology methods including Western blotting, site direct mutagenesis, endothelial cell culture systems, knock-down experiments with siRNA, invitro-angiogenesis assays and immunohistochemical studies on mouse eyes exposed to hypoxia were used to study the role of PDCL3 in regulation of VGFR2 in endometrial cells.

Results: : PDCL3 expression is upregulated by hypoxia in endothelial cells and its expression is responsible for hypoxia-induced expression of VEGFR-2. PDCL3 co-localizes with VEGFR-2 in cells and recognizes the JM domain of VEGFR-2. Over-expression of PDCL3 increases, whereas depleting its expression by siRNA in endothelial cells reduces the abundance of VEGFR-2 protein. Upregulation of PDCL3 markedly increases ligand-mediated activation of VEGFR-2.

Conclusions: : Our studies provide experimental evidence for the role of PDCL3 in governing the angiogenic pathway by controlling VEGFR-2 destruction. PDCL3 elicits its activity by rendering VEGFR-2 to a more stable protein by preventing its ubiquitylation and degradation. PDCL3 activity is required for endothelial cell proliferation and tube formation of endothelial cells and angiogenesis.

Keywords: retinal neovascularization • ischemia • pathobiology 
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