Wu, W; Zhou, G; Han, H; Huang, X; Jiang, H; Mukai, S; Kazlauskas, A; ... Lei, H; + view all Wu, W; Zhou, G; Han, H; Huang, X; Jiang, H; Mukai, S; Kazlauskas, A; Cui, J; Matsubara, JA; Vanhaesebroeck, B; Xia, X; Wang, J; Lei, H; - view fewer (2020) PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis. Diabetes , 69 (4) pp. 739-748. 10.2337/db19-0713.

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Abstract

Diabetic retinopathy is the most common microvascular complication of diabetes, characterized by the formation of 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 (HRECs) high glucose induced expression of p110, which was also expressed in ECs of fibrovascular membranes from diabetic patients. This catalytic subunit of a receptor regulated PI3K isoform  is known to be highly-enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110 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 inactivation was found to attenuate pathological retinal angiogenesis. p110 inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110 constitutes a previously-unappreciated therapeutic opportunity for diabetic retinopathy.

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