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Eunice Cheung, Ivan B Lobov, Jingtai Cao, George Yancopaulos, Carl Romano, Stanley J Wiegand; Effects of combined inhibition of VEGF and PDGFRβ using aflibercept (VEGF Trap) and anti-PDGFRβ antibody on developing retinal angiogenesis in mice.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2314.
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© ARVO (1962-2015); The Authors (2016-present)
Pharmacological inhibition of PDGFRβ prevents pericyte investment into growing blood vessels and also leads to pericyte depletion from recently formed nascent blood vessels in the developing mouse retina (E. Cheung et al., ARVO 2013). Pericytes were suggested to provide trophic support for vascular endothelial cells that mediates resistance to growth factor withdrawal of the maturing blood vessels. However, there is a significant controversy depending on the model utilized. In this study we tested the effects of VEGF blockade using aflibercept alone and in combination with anti-PDGFRβ antibody on blood vessel growth and regression in the normal retinal vascular development model.
C57Bl/6 pups were intraViTreally (IVT) injected with 5µg of a control protein (Fc), anti- PDGFRβ antibody, or aflibercept, as single agents, or in combination (anti-PDGFRβ antibody and aflibercept) at postnatal day 4 (P4). Eyes were collected at P6. The retinas were dissected and stained with antibody against NG2 (a pericyte marker), secondary antibody and GS Lectin I (for vascular endothelial cells).
IVT administration of aflibercept reduced the radial outgrowth of the superficial retinal vasculature, did not induce vessel regression, but it did induce capillary pruning. In contrast, IVT administration of anti-PDGFRβ antibody had only a subtle effect on the extent of retinal vessel outgrowth, but resulted in a nearly completely denuding of pericytes from both newly formed and extant retinal vessels. Combined treatment with both anti-PDGFRβ and aflibercept in addition to a near complete depletion of pericytes from retinal vessels and complete arrest of vessel outgrowth, also induced near complete regression of previously formed retinal vessels.
IVT administration of anti-PDGFRβ antibody nearly complete depletes pericytes from the developing vasculature, decreases capillary number and increases vessel caliber and tortuosity, but does not affect radial outgrowth of retinal vessels. In contrast, administration of aflibercept has no appreciable effect on pericyte investment, but significantly inhibits further vessel growth. Combined administration of both agents produces significantly greater effect, such that inhibition of both PDGFRβ and VEGF results in a near complete regression of the developing retinal vasculature.
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