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<p>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 (<i>NTN1</i>) 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 <i>NTN1</i> overexpression to investigate effects on BRB development and maintenance. We show that global <i>NTN1</i> overexpression converted leaky vessels at the P5 angiogenic front into a non-leaky state. In pathological settings, <i>NTN1</i> overexpression reinforced BRB integrity in oxygen-induced retinopathy (OIR), improving electroretinogram (ERG) amplitudes and rescued vascular leak in laser-induced choroidal neovascularization (CNV). <i>NTN1</i> overexpression or <i>Ntn1</i> knockout minimally and transiently affected retinal angiogenesis. Global <i>Unc5b</i> deletion phenocopied vascular leak observed in <i>Ntn1</i> deficient retinas, while angiogenesis defects differed between <i>Ntn1</i> and <i>Unc5b</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月6日

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  • Jessica Furtado,
  • Thomas E. Zapadka,
  • Hyojin Park,
  • Kevin Boyé,
  • Jonathan B. Demb,
  • Anne Eichmann

摘要

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.