# Restoring compromised blood-retina-barrier integrity with Netrin-1 overexpression

## TL;DR

This study shows that increasing Netrin-1 levels can strengthen the blood-retina barrier, potentially preventing vision loss in diseases like diabetic retinopathy and AMD.

## Contribution

The study demonstrates that Netrin-1 overexpression selectively stabilizes the blood-retina barrier without significantly affecting retinal angiogenesis.

## Key findings

- Global NTN1 overexpression reduced vascular leak in the P5 angiogenic front and pathological models like OIR and CNV.
- Netrin-1/Unc5b signaling was identified as a key pathway for BRB integrity, with distinct effects on vascular leak and angiogenesis.
- Unc5b deletion replicated vascular leak seen in Ntn1-deficient retinas, highlighting the pathway's role in BRB stability.

## Abstract

The blood-retina barrier (BRB) protects retinal neuronal function and enables vision. A compromised, leaky BRB is a hallmark of vision-threatening retinal diseases such as diabetic retinopathy (DR) and wet age-related macular degeneration (AMD) that affect millions of persons worldwide. Strategies to enhance BRB integrity hold promise as therapeutic interventions to prevent vision loss. Previous studies identified Netrin-1 (NTN1) as a key regulator of BRB stability and revealed reduced Netrin-1 signaling in DR patients, suggesting that Netrin-1 supplementation could help preserve BRB function and prevent disease progression. Herein, we used inducible genetic NTN1 overexpression to investigate effects on BRB development and maintenance. We show that global NTN1 overexpression converted leaky vessels at the P5 angiogenic front into a non-leaky state. In pathological settings, NTN1 overexpression reinforced BRB integrity in oxygen-induced retinopathy (OIR), improving electroretinogram (ERG) amplitudes and rescued vascular leak in laser-induced choroidal neovascularization (CNV). NTN1 overexpression or Ntn1 knockout minimally and transiently affected retinal angiogenesis. Global Unc5b deletion phenocopied vascular leak observed in Ntn1 deficient retinas, while angiogenesis defects differed between Ntn1 and Unc5b knockouts. These findings establish Netrin-1 as a promising therapeutic target for preventing BRB breakdown in retinal vascular diseases and suggest that reinforcing the Netrin-1/Unc5b signaling pathway may provide a strategy to selectively stabilize the BRB.

The online version contains supplementary material available at 10.1007/s00018-025-05903-6.