Involvement of Bradykinin B2 Receptor in Pathological Vascularization in Oxygen-Induced Retinopathy in Mice and Rabbit Cornea.

Erika Terzuoli,Sandra Donnini,Ginevra Nannelli,Antonio Giachetti,Marina Ziche,Lucia Morbidelli

doi:10.3390/ijms19020330

Erika Terzuoli, Sandra Donnini + Show 4 more

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https://doi.org/10.3390/ijms19020330

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Abstract

The identification of components of the kallikrein–kinin system in the vitreous from patients with microvascular retinal diseases suggests that bradykinin (BK) signaling may contribute to pathogenesis of retinal vascular complications. BK receptor 2 (B2R) signaling has been implicated in both pro-inflammatory and pro-angiogenic effects promoted by BK. Here, we investigated the role of BK/B2R signaling in the retinal neovascularization in the oxygen-induced retinopathy (OIR) model. Blockade of B2R signaling by the antagonist fasitibant delayed retinal vascularization in mouse pups, indicating that the retinal endothelium is a target of the BK/B2R system. In the rabbit cornea assay, a model of pathological neoangiogenesis, the B2 agonist kallidin induced vessel sprouting and promoted cornea opacity, a sign of edema and tissue inflammation. In agreement with these results, in the OIR model, a blockade of B2R signaling significantly reduced retinal neovascularization, as determined by the area of retinal tufts, and, in the retinal vessel, it also reduced vascular endothelial growth factor and fibroblast growth factor-2 expression. All together, these findings show that B2R blockade reduces retinal neovascularization and inhibits the expression of proangiogenic and pro-inflammatory cytokines, suggesting that targeting B2R signaling may be an effective strategy for treating ischemic retinopathy.

Highlights

The kallikrein–kinin system (KKS) has long been recognized as a key player of inflammatory processes in various organs [1]
We investigated the role of BK/B2R signaling in the retinal neovascularization in the oxygen-induced retinopathy (OIR) model
In the rabbit cornea assay, a model of pathological neoangiogenesis, the B2 agonist kallidin induced vessel sprouting and promoted cornea opacity, a sign of edema and tissue inflammation. In agreement with these results, in the OIR model, a blockade of B2R signaling significantly reduced retinal neovascularization, as determined by the area of retinal tufts, and, in the retinal vessel, it reduced vascular endothelial growth factor and fibroblast growth factor-2 expression. These findings show that B2R blockade reduces retinal neovascularization and inhibits the expression of proangiogenic and pro-inflammatory cytokines, suggesting that targeting B2R signaling may be an effective strategy for treating ischemic retinopathy

Summary

Introduction

The kallikrein–kinin system (KKS) has long been recognized as a key player of inflammatory processes in various organs [1]. Components of the KKS, including plasma kallikrein, factor XII and high-molecular-weight kininogen (HK), are increased in the vitreous of patients with diabetic retinopathy and have been associated with retinal vascular inflammation and neoangiogenesis [2]. Bradykinin (BK), generated by the plasma kallikrein proteolytic activity on HK, primarily mediates KKS actions. BK exerts potent pro-inflammatory and pro-angiogenic effects through the activation of two G-protein-coupled receptors, BK receptor 1 and 2 (B1R, B2R), widely expressed in vascular tissues, including retinal vessels [3]. BK/B2R signaling was reported to induce leakage in post-capillary venules of rat mesentery, and angioedema in both C1-INH null mice and in humans [6,7]

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