Vascular Endothelial Growth Factor Signaling in Models of Oxygen-Induced Retinopathy: Insights Into Mechanisms of Pathology in Retinopathy of Prematurity.

Aniket Ramshekar,M Elizabeth Hartnett

doi:10.3389/fped.2021.796143

Abstract

Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide. Blindness can occur from retinal detachment caused by pathologic retinal angiogenesis into the vitreous, termed intravitreal neovascularization (IVNV). Although agents that interfere with the bioactivity of vascular endothelial growth factor (VEGF) are now used to treat IVNV, concerns exist regarding the identification of optimal doses of anti-VEGF for individual infants and the effect of broad VEGF inhibition on physiologic angiogenesis in external organs or in the retina of a preterm infant. Therefore, it is important to understand VEGF signaling in both physiologic and pathologic angiogenesis in the retina. In this manuscript, we review the role of receptors that interact with VEGF in oxygen-induced retinopathy (OIR) models that represent features of ROP pathology. Specifically, we discuss our work regarding the regulation of VEGFR2 signaling in retinal endothelial cells to not only reduce severe ROP but also facilitate physiologic retinal vascular and neuronal development.

Highlights

Retinopathy of prematurity (ROP) remains a leading cause of blindness in children worldwide despite advances in neonatal care [1]
The disparity in studies might be because PlGF1 does not bind VEGFR2 monomers [41], and VEGFR2related signaling is important in intravitreal neovascularization (IVNV)
Studies in oxygen-induced retinopathy (OIR) models that recapitulate aspects of human ROP have provided insights into vascular endothelial growth factor (VEGF) signaling through VEGF receptors (VEGFRs) and neuropilins in specific cell types

Summary

INTRODUCTION

Retinopathy of prematurity (ROP) remains a leading cause of blindness in children worldwide despite advances in neonatal care [1]. The disparity in studies might be because PlGF1 does not bind VEGFR2 monomers [41], and VEGFR2related signaling is important in IVNV (see The role of vascular endothelial growth factor receptor 2 in models of retinopathy of prematurity section) In support of this notion, Zeng et al observed disordered divisions of mouse embryonic stem cell-derived vessels from VEGFR1 knockout mice (flt1−/−) [42]. There was no difference in a- or b-wave amplitudes assessed by fullfield electroretinography in adult rats compared with littermate controls [47] These findings contrasted with earlier studies in which Müller cell-derived VEGFA knockdown by lentiviral vectors in the rat OIR led to retinal thinning, [32] and intravitreal VEGF-Trap delayed physiologic retinal vascular development in the dog OIR model [26] compared with respective controls. The data suggest that a certain dose or agent that regulates VEGF-mediated signaling triggered through VEGFR2 in retinal endothelial cells might be a possible therapeutic approach to inhibit IVNV, facilitate physiologic retinal vascular development, and reduce the likelihood of recurrent IVNV in ROP

THE ROLE OF NEUROPILINS IN MODELS OF RETINOPATHY OF PREMATURITY

DISCUSSION