April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
The Dll4/Notch Pathway Controls Blood Vessel Remodeling and Regression by Modulating Vasoconstriction and Blood Flow Independently of VEGF-A
Author Affiliations & Notes
  • I. B. Lobov
    Ophthalmology, Regeneron Pharmaceuticals Inc, Tarrytown, New York
  • E. Cheung
    Ophthalmology, Regeneron Pharmaceuticals, Tarrytown, New York
  • G. Yancopoulos
    Ophthalmology, Regeneron Pharmaceuticals Inc, Tarrytown, New York
  • S. J. Wiegand
    Ophthalmic Sciences, Regeneron Pharmaceuticals, Inc, Tarrytown, New York
  • Footnotes
    Commercial Relationships  I.B. Lobov, Regeneron Pharmaceuticals, Inc., E; E. Cheung, Regeneron Pharmaceuticals, Inc., E; G. Yancopoulos, Regeneron Pharmaceuticals, Inc., E; S.J. Wiegand, Regeneron Pharmaceuticals, Inc., E.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 3334. doi:
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      I. B. Lobov, E. Cheung, G. Yancopoulos, S. J. Wiegand; The Dll4/Notch Pathway Controls Blood Vessel Remodeling and Regression by Modulating Vasoconstriction and Blood Flow Independently of VEGF-A. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3334.

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

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Abstract

Purpose: : The Dll4/Notch pathway plays a critical role in both normal and pathological angiogenesis [Lobov et al., PNAS 2007; IOVS 2007 48: E-3432], but currently very little is known about roles of this pathway in mediating other aspects of vascular function and remodeling. We have recently shown that Dll4/Notch inhibition significantly reduces oxygen-induced vasoobliteration in the retinas of neonatal mice [IOVS 2008 49: E-3296]. Here we compare the effects of modulating Dll4 and VEGF signaling on capillary remodeling and regression.

Methods: : Dll4/Notch signaling was blocked by systemic or intravitreal (ITV) injection of Dll4-Fc. VEGF signaling was modulated by ITV injection of VEGF-A or VEGF Trap. Control mice received injections of human Fc. Vasoobliteration was induced by exposing mice to 75%O2 on postnatal day 7 (P7). Tomato lectin labeled with Texas Red was infused intracardially to assess blood vessel patency. Retinas were stained with FITC-labeled GS lectin I to visualize the vasculature. Changes in retinal gene expression profiles were evaluated by microarray and real-time PCR.

Results: : Administration of Dll4-Fc prior to hyperoxia significantly reduced blood vessel loss by maintaining blood flow crucial for survival of newly formed microvessels. Though VEGF-A also ameliorated hyperoxia induced vasoobliteration, it produced marked abnormalities in blood vessel structure that were not evident with Dll4 inhibition. Moreover, inhibition of VEGF-A under normoxic conditions did not result in a pervasive loss of capillaries in the central retina, demonstrating that reduced VEGF-A signaling is not the proximate cause of capillary regression induced by hyperoxia. Pharmacological modulation of Dll4/Notch and VEGF signaling also produced distinct patterns of changes in vasoactive genes.

Conclusions: : Dll4/Notch pathway regulates multiple aspects of blood vessel remodeling in the retina, including modulation of blood vessel regression by regulating vasoconstriction and blood flow. Moreover, Dll4/Notch and VEGF pathways mediate discrete and largely independent functions in the post-angiogenic vasculature.

Keywords: retina • retinal neovascularization • vascular occlusion/vascular occlusive disease 
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