March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Involvement of Lysosomal Proteases in VEGF-C Down-Regulation of VEGFR-3
Author Affiliations & Notes
  • Jin-Hong Chang
    Ophthalmology and Visual Sciences, Univ of Illinois at Chicago, Chicago, Illinois
  • Kyu-Yeon Han
    Ophthalmology and Visual Sciences, Univ of Illinois at Chicago, Chicago, Illinois
  • Dimitri T. Azar
    Ophthalmology and Visual Sciences, Univ of Illinois at Chicago, Chicago, Illinois
  • Footnotes
    Commercial Relationships  Jin-Hong Chang, None; Kyu-Yeon Han, None; Dimitri T. Azar, None
  • Footnotes
    Support  NIH Grant EY 021886, EY10101 (DTA), EY01792 (DTA) and an unrestricted grant from Research to Prevent Blindness, New York, NY. The authors report no proprietary interest.
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 2394. doi:
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      Jin-Hong Chang, Kyu-Yeon Han, Dimitri T. Azar; Involvement of Lysosomal Proteases in VEGF-C Down-Regulation of VEGFR-3. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2394.

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Abstract

Purpose: : To characterize the involvement of Lysosomal Proteases in VEGF-C Down-Regulation of VEGFR-3

Methods: : Lymphatic endothelial cells were stimulated with vascular endothelial growth factor (VEGF-C, -D, C156S, and VEGF-A) at various (vague) time-points. Unstimulated and stimulated cells were lysed with RIPA buffer and cellular lysates were immunoblotted with anti-VEGFR-3, phosphor-tyrosine, Erk, jnk, and p38 antibodies. Lymphatic cells were also stimulated with VEGF-C in the presence of a VEGF-C trap, Notch activator, inhibitor, VEGF Receptor-3 (VEGFR-3) kinase inhibitor, LPE (leupeptin, pepstatin, and E64 inhibitor), gamma-secretase inhibitor, or autophagy inhibitor Cellular lysates were immunobloted with anti-VEGFR-3 antibodies.

Results: : VEGF-C induces down-regulation of VEGFR-3, which is important for lymphangiogenesis, but incompletely understood. Here, we demonstrate that VEGF-C, -D, and C156S, but not VEGF-A, down-regulate VEGFR-3. VEGF-C stimulated VEGFR-3 tyrosyl phosphorylation and transient phosphorylation of ERK, p38, and c-Jun N-terminal kinases in lymphatic endothelial cells. VEGF-C-induced VEGFR-3 down-regulation was blocked by a VEGF-C trap, VEGFR-3 kinase inhibitor, and LPE inhibitor, but was unaffected by Notch 1 activator and gamma-secretase inhibitors.

Conclusions: : Our findings indicate that VEGF-C down-regulates VEGFR-3 in lymphatic endothelial cells through VEGFR-3 kinase activation and, in part, via the lysosomal degradation pathway.

Keywords: cornea: basic science • neovascularization • cornea: epithelium 
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