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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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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.
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.
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.
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.
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