Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis

Amino acid metabolism in vascular endothelium is important for sprouting angiogenesis. SLC38A5 (solute carrier family 38 member 5), an amino acid (AA) transporter, shuttles neutral AAs across cell membrane, including glutamine, which may serve as metabolic fuel for proliferating endothelial cells (ECs) to promote angiogenesis. Here we found thatSlc38a5is highly enriched in normal retinal vascular endothelium, and more specifically in pathological sprouting neovessels.Slc38a5is suppressed in retinal blood vessels fromLrp5^-/-andNdp^y/-mice, both genetic models of defective retinal vascular development with Wnt signaling mutations. Additionally,Slc38a5transcription is directly regulated by Wnt/β-catenin signaling. Genetic deficiency ofSlc38a5in mice substantially delays retinal vascular development and suppresses pathological neovascularization in oxygen-induced retinopathy modeling ischemic proliferative retinopathies. Inhibition ofSLC38A5in retinal vascular ECs impairs EC proliferation and angiogenic function, suppresses glutamine uptake, and dampens vascular endothelial growth factor receptor 2 (VEGFR2). Together these findings suggest that SLC38A5 is a new metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in ECs.