PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis

Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110 delta, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform delta is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110 delta activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110 delta inactivation was found to attenuate pathological retinal angiogenesis. p110 delta inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110 delta constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.