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I. B. Lobov, E. Cheung, G. D. Yancopoulos, S. J. Wiegand; Dll4/Notch Inhibition Prevents Retinal Capillary Regression. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3296.
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Notch signaling pathways control cell fate determination and morphogenesis in many tissues and organs. Dll4 signaling through Notch receptors has been recently implicated in control of angiogenesis. We have previously reported that pharmacologic inhibition of Dll4, or deletion of a single Dll4 allele, resulted in a significant increase in vessel sprouting and endothelial cell proliferation during retinal vascular development, indicating that Dll4 is a potent endogenous inhibitor of angiogenesis [IOVS 2006 47: E-3877; Lobov et al., PNAS 2007]. Moreover, pharmacological inhibition of Dll4/Notch signaling was shown to attenuate ectopic, pathological neovascularization while improving retinal revascularization in the murine model of oxygen-induced ischemic retinopathy (OIR) [IOVS 2007 48: E-3432]. The present studies evaluated the effects of Dll4/Notch inhibition in the murine model of oxygen-induced vasoobliteration.
Dll4/Notch signaling was blocked by intravitreal injection of Dll4-Fc (a soluble decoy ligand) or a polyclonal, neutralizing antibody against Dll4 on postnatal day 8 (PN8). Control mice received an intravitreal injection of human Fc. Cohorts of animals were then either immediately exposed to hyperoxia (Smith et al., IOVS 1994), or continued to be raised in room air. Lycopersicon esculentum lectin labeled with Texas Red was injected into the left cardiac ventricle on day PN9 and allowed to circulate for 5 minutes to assess blood vessel patency. Retinas were dissected, stained with FITC-labeled Griffonia simplicifolia lectin I to visualize the vasculature and flat mounted. Changes in retinal gene expression profiles were evaluated using microarray analysis.
Pharmacological inhibition of Dll4 using Dll4-Fc or anti-Dll4 neutralizing antibody prevented hyperoxia-induced retinal capillary regression and also increased capillary density in the central retina of animals raised under normoxic conditions. Microarray analysis confirmed specific suppression of Notch signaling pathway by Dll4-Fc and revealed multiple genes whose expression was significantly altered, including vasoactive genes controlling blood vessel constriction and dilation.
Activation of the Dll4/Notch pathway appears to regulate multiple aspects of blood vessel remodeling, by promoting blood vessel regression, as well as inhibiting endothelial cell proliferation and angiogenic sprouting under normal and pathological conditions. Thus, application of Dll4/Notch inhibitors may have beneficial effects in diseases characterized by blood vessel loss and/or insufficient angiogenesis.
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