Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity
Shu-Ching Shih, … , Nan Liu, Lois E.H. Smith
Shu-Ching Shih, … , Nan Liu, Lois E.H. Smith
Published July 1, 2003
Citation Information: J Clin Invest. 2003;112(1):50-57. https://doi.org/10.1172/JCI17808.
View: Text | PDF
Article Aging

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

×

Figure 6

Options: View larger image (or click on image) Download as PowerPoint
Activation of VEGFR-1 by PlGF-1 does not increase normal retinal vessel ...
Activation of VEGFR-1 by PlGF-1 does not increase normal retinal vessel growth or revascularization. (a) Intravitreal injections at P3 of control (BSS) in one eye and PlGF-1 in the contralateral eye (n = 6). Retinal vessel growth area was measured in whole mounts at P5. PlGF-1–injected eyes had a mean of 41.67% ± 5.63% of the retina vascularized. Similarly, 42.18% ± 8.60% of the BSS-injected contralateral control eyes were vascularized (P = 0.91). Results are representative of two independent experiments. (b) Vessel revascularization was measured in P15 mice after induction of vessel loss by oxygen (P7–P12) followed by intravitreal injections of BSS at P13 in one eye and PlGF-1 in the contralateral eye. PlGF-1–injected eyes were 26.32% ± 2.62% vascularized; similarly, BSS-treated contralateral control eyes were 26.29% ± 2.86% vascularized (n = 6, P = 0.99). Results are representative of two independent experiments. (c) In eyes with oxygen-induced retinopathy, the mean number of vascular nuclei extending into the vitreous at P17 in ten retinal cross sections per eye (n = 8 eyes) was counted after intravitreal injections of BSS at P13 (after 5 days of 75% O2 treatment, from P7 to P12) in one eye and PlGF-1 in the contralateral eye. BSS- and PlGF-1–injected eyes showed means of 9.98 and 9.96 vascular nuclei (P = 0.61), respectively, indicating no stimulation of proliferation by PlGF-1.