PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis

Area of Science:

• Ophthalmology
• Endocrinology
• Molecular Biology

Background:

• Diabetic retinopathy is a leading cause of blindness and a microvascular complication of diabetes.
• Advanced diabetic retinopathy features vitreal fibrovascular membranes composed of various cells, including endothelial cells (ECs).
• Current therapeutic strategies for diabetic retinopathy are limited, necessitating novel approaches.

Purpose of the Study:

• To investigate the role of p110δ, a catalytic subunit of phosphoinositide 3-kinase (PI3K) isoform δ, in diabetic retinopathy.
• To determine if p110δ activity in retinal microvascular ECs influences pathological angiogenesis.
• To explore the potential of p110δ antagonism as a therapeutic strategy for diabetic retinopathy.

Main Methods:

• Cultured human retinal microvascular ECs were exposed to high glucose conditions.
• Genetic and pharmacological methods were used to inhibit p110δ activity in ECs.
• A mouse model of oxygen-induced retinopathy was employed to study retinal angiogenesis in vivo.
• Expression levels of p110δ and Akt activation were assessed.

Main Results:

• High glucose upregulated p110δ expression in cultured human retinal microvascular ECs.
• p110δ was also found in ECs of fibrovascular membranes from diabetic patients.
• p110δ activity was crucial for Akt activation, proliferation, migration, and tube formation in ECs stimulated by growth factors.
• Inhibition of p110δ attenuated pathological retinal angiogenesis in a mouse model.

Conclusions:

• p110δ plays a significant role in regulating EC functions relevant to diabetic retinopathy pathogenesis.
• Antagonizing p110δ presents a promising, previously unrecognized therapeutic avenue for treating diabetic retinopathy.
• Existing p110δ inhibitors approved for B-cell malignancies could potentially be repurposed for diabetic retinopathy treatment.