Role of TGF-Beta1/SMAD2/3 Pathway in Retinal Outer Deep Vascular Plexus and Photoreceptor Damage in Rat 50/10 Oxygen-Induced Retinopathy.

Huijuan Li,Ruibin Zhao,Li Jiang,Lijuan Qian,Ruyuan Zhu

doi:10.1155/2019/4072319

Abstract

In retinopathy of prematurity (ROP), outer deep vascular plexus (oDVP) was the emerging field, and the mechanisms of photoreceptor dysfunction remained to be explored. ODVP and photoreceptors were related, with oDVP being part of the supplier of oxygen and nutrients to photoreceptors, while their possible relationship in ROP was not clear. TGF-beta1 has been reported indispensable in oDVP development and altered in ROP patients and animal models. We hypothesized that the TGF-beta1 alteration in rat 50/10 oxygen-induced retinopathy (OIR) model contributed to oDVP malformation and exerted consequent effects on photoreceptor development. We first explored the profile of oDVP development in rat after birth and compared the expression of TGF-beta1 and pSMAD2/3 in Normoxia and OIR groups. Afterwards, the inhibitor of the pathway, LY364947, was used to establish the OIR, OIR+LY364947, Normoxia, and Normoxia+LY364947 groups. The oDVP and photoreceptor were examined by Isolectin B4 staining, western-blot of CD31 and Rho, and electron microscopy. ODVP sprouted at postnatal day 10 (D10) and reached the edge of retina at D14. The TGF-beta1/SMAD2/3 pathway was compromised during the critical period of oDVP development. The inhibitor simulated the oDVP retardation, pericyte, and photoreceptor malformation in the Normoxia+LY364947 group and might further compromise the development of oDVP and photoreceptor in the OIR+LY364947 group. The inhibition of the TGF-beta1/SMAD2/3 pathway indicated its critical role in oDVP malformation and photoreceptor damage, suggesting a possible therapeutic target of ROP treatment.

Highlights

Retinopathy of prematurity (ROP) is considered a disease of abnormal retinal vascularization, caused by adverse events, such as hyperoxia, hypoxia, inflammation, and malnutrition [1]
We explored the development of vasculatures, including the superficial vascular plexus (SVP, green), inner deep vascular plexus, and outer deep vascular plexus
In the Normoxia+LY364947 retinas, total vascular retardation was indicated by CD31 downregulation; the development of the outer deep vascular plexus (oDVP) and pericyte was blocked, as shown in the flat-mounting staining and electron microscopy in the outer plexiform layer (OPL) region; photoreceptor growth was found to be deteriorated according to the results of electron microscopy and decreased Rho expression

Summary

Introduction

Retinopathy of prematurity (ROP) is considered a disease of abnormal retinal vascularization, caused by adverse events, such as hyperoxia, hypoxia, inflammation, and malnutrition [1]. Most studies focused on vascular pathologies, including growth retardation and abnormal neovascularization, but little attention has been drawn to neuron damage. The rod photoreceptor has been confirmed vulnerable and its malformation and malfunction persist years after ROP resolution [2,3,4,5,6]. A few studies have explored the mechanisms underlying photoreceptor damage [7]. The relationship between photoreceptor and oDVP has been explored in diabetic retinopathy (DR). Clinical data has confirmed the contributing role of oDVP nonperfusion in photoreceptor damage in DR [8,9,10], but their possible relationship has not been explored in ROP

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