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W. Xiao, S.A. Vinores, D. Collen, P. Carmeliet, P.A. Campochiaro; Retinal Vascular Permeability Is Regulated by VEGFR1 and VEGFR2 . Invest. Ophthalmol. Vis. Sci. 2006;47(13):503.
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VEGF has been thought to promote vascular permeability solely through VEGF receptor–2 (VEGFR2), but recent findings have suggested that VEGFR1 is also implicated. Using highly specific antibodies to VEGFR2 and placental growth factor (PlGF), which binds to VEGFR1, but not VEGFR2, we hope to establish whether both receptor isotypes function in mediating retinal vascular permeability.
VEGF transgenic mice (V6) received intraperitoneal (ip) injections of 40µg/g body weight VEGFR2 antibody (Thromb–X, Leuven, Belgium) every 3 days, beginning at postnatal day 5 (P5) and the blood–retinal barrier (BRB) was assessed using 3H–mannitol at P17. Oxygen–induced ischemic retinopathy (OIR) was generated in C57BL/6 mice by incubating them in 75% oxygen from P7–12 and then removing them to the relative hypoxia of room air. Mice with OIR and littermate controls received ip injections of 0.25 or 0.5mg anti–PlGF antibody on P12 and P14 or 40µg/g anti–VEGFR2 antibody (Thromb–X) on P12 and P15 and the BRB was assessed on P17.
Anti–VEGFR2 antibody suppressed retinal vascular leakage in VEGF transgenic mice (retina/lung leakage ratio [RLLR] decreased 35%; retina/renal leakage ratio [RRLR] decreased 54%; p<0.001) and mice with OIR (RLLR and RRLR decreased 17%; p=0.01). Anti–PlGF antibody at a dosage of 0.5mg, but not lower, suppressed retinal vascular leakage in mice with OIR (RLLR decreased 33%; RRLR decreased 41%; p<0.002).
The suppression of BRB breakdown by anti–VEGFR2 in VEGF transgenic mice and mice with OIR confirmed that VEGF promotes retinal vascular leakage via VEGFR2. Since anti–PlGF mediated neutralization of PlGF, which binds to VEGFR1, but not VEGFR2, also suppressed BRB breakdown, this provides evidence that VEGFR1 is also implicated in promoting retinal vascular permeability. Therefore, in ocular disorders that upregulate VEGF and/or PlGF, such as diabetic retinopathy or other ischemic retinopathies or age–related macular degeneration, targeting a single VEGF receptor isotype to prevent macular edema may not yield optimal results.
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