Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity
Shu-Ching Shih, Meihua Ju, Nan Liu, Lois E.H. Smith
Shu-Ching Shih, Meihua Ju, Nan Liu, Lois E.H. Smith
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Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity

Abstract

Oxygen administration to immature neonates suppresses VEGF-A expression in the retina, resulting in the catastrophic vessel loss that initiates retinopathy of prematurity. To investigate the mechanisms responsible for survival of blood vessels in the developing retina, we characterized two VEGF-A receptors, VEGF receptor–1 (VEGFR-1, also known as Flt-1) and VEGF receptor–2 (VEGFR-2, also known as Flk-1). Surprisingly, these two VEGF-A receptors differed markedly during normal retinal development in mice. At 5 days postpartum (P5), VEGFR-1 protein was colocalized with retinal vessels, whereas VEGFR-2 was detected only in the neural retina. Real-time RT-PCR identified a 60-fold induction of VEGFR-1 mRNA in retina from P3 (early vascularization) to P26 (fully vascularized), and no significant change in VEGFR-2 mRNA expression. Placental growth factor-1 (PlGF-1), which exclusively binds VEGFR-1, decreased hyperoxia-induced retinal vaso-obliteration from 22.2% to 5.1%, whereas VEGF-E, which exclusively binds VEGFR-2, had no effect on blood vessel survival. Importantly, under the same conditions, PlGF-1 did not increase vasoproliferation during (a) normal vessel growth, (b) revascularization following hyperoxia-induced ischemia, or (c) the vasoproliferative phase, indicating a selective function supporting blood vessel survival. We conclude that VEGFR-1 is critical in maintaining the vasculature of the neonatal retina, and that activation of VEGFR-1 by PlGF-1 is a selective strategy for preventing oxygen-induced retinal ischemia without provoking retinal neovascularization.

Authors

Shu-Ching Shih, Meihua Ju, Nan Liu, Lois E.H. Smith

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PlGF-1, but not VEGF-E, prevents hyperoxia-induced retinal vessel loss, ...
PlGF-1, but not VEGF-E, prevents hyperoxia-induced retinal vessel loss, thus implicating VEGFR-1 in survival. PlGF-1: P8 FITC-dextran–perfused retinal flat-mount retina from a representative control mouse treated with room air (normoxia) (a) or a mouse given hyperoxic treatment (75% O2 for 17 hours at P7–P8) after intravitreal injection on P7 of (b) control BSS in one eye and (c) the VEGFR-1–specific ligand PlGF-1 in the contralateral eye. Vessels delineated with FITC show that PlGF-1 confers significant protection from oxygen-induced vessel loss compared with BBS control. (d) Analysis of nonvascularized area shows a greater than fourfold difference between eyes treated with PlGF-1 (22.2% ± 3.4% vascularized area) and eyes treated with BSS (5.1% ± 1.2%) (n = 6, P < 0.001). VEGF-E: FITC-dextran–perfused retinal flat mount of P8 control retina from representative room air–treated mouse (e) or oxygen-exposed mouse after intravitreal injections at P7 of (f) control BSS in one eye and (g) VEGFR-2–specific ligand VEGF-E in the contralateral eye. (h) Analysis of nonvascularized area shows no significant difference between VEGF-E– and BSS-treated eyes (n = 6, P = 0.87). Results are representative of two independent experiments.