PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis

Diabetes. 2020 Apr;69(4):736-748. doi: 10.2337/db19-0713. Epub 2020 Jan 8.

Abstract

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 p110δ, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform δ is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110δ 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, p110δ inactivation was found to attenuate pathological retinal angiogenesis. p110δ inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110δ constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Class I Phosphatidylinositol 3-Kinases / metabolism*
  • Diabetic Retinopathy / metabolism*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelial Growth Factors / pharmacology
  • Fibroblast Growth Factor 2 / pharmacology
  • Glucose / pharmacology
  • Immunohistochemistry
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Proto-Oncogene Proteins c-akt / metabolism
  • Retinal Neovascularization / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Vascular Endothelial Growth Factor A / pharmacology

Substances

  • Endothelial Growth Factors
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • Class I Phosphatidylinositol 3-Kinases
  • Pik3cd protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glucose