Periostin and tenascin-C interaction promotes angiogenesis in ischemic proliferative retinopathy

Yuki Kubo,Mitsuru Arima,Koh-Hei Sonoda,Takahito Nakama,Masatoshi Haruta,Kenichiro Mori,Shigeo Yoshida,Shintaro Nakao,Yoshiyuki Kobayashi,Keijiro Ishikawa,Toshio Hisatomi

doi:10.1038/s41598-020-66278-1

Yuki Kubo, Mitsuru Arima + Show 9 more

Open Access

https://doi.org/10.1038/s41598-020-66278-1

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Journal: Scientific Reports	Publication Date: Jun 9, 2020
Citations: 17	License type: open-access

Affiliation: Kyushu University, Kurume University

Abstract

Ischemic proliferative retinopathy (IPR), such as proliferative diabetic retinopathy (PDR), retinal vein occlusion and retinopathy of prematurity is a major cause of vision loss. Our previous studies demonstrated that periostin (PN) and tenascin-C (TNC) are involved in the pathogenesis of IPR. However, the interactive role of PN and TNC in angiogenesis associated with IPR remain unknown. We found significant correlation between concentrations of PN and TNC in PDR vitreous humor. mRNA and protein expression of PN and TNC were found in pre-retinal fibrovascular membranes excised from PDR patients. Interleukin-13 (IL-13) promoted mRNA and protein expression of PN and TNC, and co-immunoprecipitation assay revealed binding between PN and TNC in human microvascular endothelial cells (HRECs). IL-13 promoted angiogenic functions of HRECs. Single inhibition of PN or TNC and their dual inhibition by siRNA suppressed the up-regulated angiogenic functions. Pathological pre-retinal neovessels of oxygen-induced retinopathy (OIR) mice were attenuated in PN knock-out, TNC knock-out and dual knock-out mice compared to wild-type mice. Both in vitro and in vivo, PN inhibition had a stronger inhibitory effect on angiogenesis compared to TNC inhibition, and had a similar effect to dual inhibition of PN and TNC. Furthermore, PN knock-out mice showed scant TNC expression in pre-retinal neovessels of OIR retinas. Our findings suggest that interaction of PN and TNC facilitates pre-retinal angiogenesis, and PN is an effective therapeutic target for IPR such as PDR.

Highlights

Ischemic proliferative retinopathy (IPR), such as proliferative diabetic retinopathy (PDR), retinal vein occlusion and retinopathy of prematurity is a major cause of vision loss
We investigated the inhibitory effects of PN and/or TNC inhibition on retinal angiogenesis in mice model of oxygen-induced retinopathy and in vitro human retinal microvascular endothelial cells (HRECs) to identify therapeutic targets to control fibrovascular proliferation in IPR such as PDR
To examine the correlation between PN, TNC and FN, we quantified concentrations of PN, TNC and FN in the vitreous humor obtained from patients with PDR and non-diabetic controls, macular hole (MH) and epiretinal membrane (ERM) by ELISA

Summary

Introduction

Ischemic proliferative retinopathy (IPR), such as proliferative diabetic retinopathy (PDR), retinal vein occlusion and retinopathy of prematurity is a major cause of vision loss. Accumulated evidence suggest that ECM components including PN, TNC and fibronectin (FN) that is a well-characterized molecule, promotes physiological and pathological retinal angiogenesis[21,22,23,24,25,26] These proteins interact with each other and form the ECM meshwork architecture during the process of scaffold remodeling in angiogenesis and fibrosis, such as bronchial asthma and intrahepatic cholangiocarcinoma[27,28,29,30]. We investigated the inhibitory effects of PN and/or TNC inhibition on retinal angiogenesis in mice model of oxygen-induced retinopathy and in vitro human retinal microvascular endothelial cells (HRECs) to identify therapeutic targets to control fibrovascular proliferation in IPR such as PDR

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