Region-Specific Roles of TGF-β2 and Angiotensin II in Fibrotic and Inflammatory Remodeling of the Optic Nerve Head

TL;DR

This study explores how TGF-β2 and Angiotensin II affect fibrosis and inflammation in eye tissues, revealing their distinct roles in glaucoma-related damage.

Contribution

The study identifies region-specific functions of TGF-β2 and AngII in fibrotic and inflammatory remodeling of the optic nerve head.

Findings

TGF-β2 induces fibrosis across all scleral regions, marked by increased ECM proteins.

AngII causes region-specific inflammation, especially in lamina cribrosa and peripapillary sclera.

Blocking AngII reduces glial activation and protects retinal ganglion cells better than TGF-β2 inhibition.

Abstract

This study investigated the region-specific roles of transforming growth factor-β2 (TGF-β2) and angiotensin II (AngII) in extracellular matrix (ECM) remodeling and inflammatory responses within scleral tissues surrounding the optic nerve head (ONH), using primary human fibroblasts from posterior sclera, peripapillary sclera (ppScl), and fibroblast-like cells from lamina cribrosa (LC). In vivo validation was performed in a chronic ocular hypertension rat model. Fibrotic and inflammatory markers were analyzed by Western blotting, quantitative PCR, and immunocytochemistry following TGF-β2 or AngII stimulation, and in vivo effects were assessed after subtenon injection of pathway-specific inhibitors. TGF-β2 induced robust upregulation of α-smooth muscle actin, collagen type I, and fibronectin across all scleral regions, whereas AngII elicited regionally confined pro-inflammatory responses, particularly in the LC and ppScl, characterized by increased cyclooxygenase-2 expression. Inhibition of either pathway reduced ECM deposition in vivo, but only AngII blockade significantly attenuated glial activation and preserved retinal ganglion cells. These findings demonstrate that TGF-β2 predominantly drives fibrosis, while AngII promotes region-specific neuroinflammation, and that inflammation, rather than fibrosis alone, plays a critical role in glaucomatous neurodegeneration. Targeting both fibrotic and inflammatory mechanisms in a region-specific manner may offer improved neuroprotection in glaucoma.

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