Disrupting VE-cadherin Y685 phosphorylation inhibits development of experimental diabetic and prediabetic retinopathy

Area of Science:

• Ophthalmology
• Vascular Biology
• Diabetic Complications

Background:

• Diabetic retinopathy (DR) is characterized by early retinal vascular barrier breakdown and pericyte loss, with initiating molecular events poorly understood.
• Vascular endothelial cadherin (VE-cadherin), crucial for endothelial integrity, is reduced in diabetic/prediabetic mouse retinas, preceding pericyte loss.
• Nucleoside diphosphate kinase B (NDPKB) deficiency is implicated in DR pathogenesis.

Purpose of the Study:

• To investigate the role of VE-cadherin phosphorylation in diabetic retinopathy.
• To identify molecular mechanisms linking high glucose and NDPKB deficiency to endothelial dysfunction.
• To explore therapeutic strategies targeting VE-cadherin in diabetic retinopathy.

Main Methods:

• In vitro studies using high glucose (HG) and NDPKB-deficient endothelial cells.
• VE-cadherin Y685F mutation to prevent phosphorylation.
• In vivo studies using VE-cadherin Y685F-knockin mice under diabetic/prediabetic conditions.
• Retinal proteomics analysis.

Main Results:

• HG and NDPKB deficiency induced VE-cadherin Y685 phosphorylation, internalization, and increased angiopoietin 2 (Ang2) via the hexosamine biosynthesis pathway.
• VE-cadherin Y685F mutation blocked these effects, preventing endothelial barrier dysfunction and pericyte loss.
• In vivo, Y685F-knockin mice showed protection against diabetes-induced vascular hyperpermeability, reduced O-GlcNAcylation and Ang2, and preserved neuronal function.
• Proteomics revealed restoration of neurovascular and mitochondrial pathways in Y685F mice.

Conclusions:

• VE-cadherin Y685 phosphorylation is a key mediator of high glucose- and NDPKB deficiency-induced retinal vascular damage.
• Targeting VE-cadherin Y685 phosphorylation presents a promising therapeutic strategy for diabetic and prediabetic retinopathy.
• Maintaining retinal vascular integrity through this approach can preserve neuronal function.