Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis

Abstract

Amino acid (AA) metabolism in vascular endothelium is important for sprouting angiogenesis. SLC38A5 (solute carrier family 38 member 5), an 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 that Slc38a5 is highly enriched in normal retinal vascular endothelium, and more specifically, in pathological sprouting neovessels. Slc38a5 is suppressed in retinal blood vessels from Lrp5−/− and Ndpy/− mice, both genetic models of defective retinal vascular development with Wnt signaling mutations. Additionally, Slc38a5 transcription is regulated by Wnt/β-catenin signaling. Genetic deficiency of Slc38a5 in mice substantially delays retinal vascular development and suppresses pathological neovascularization in oxygen-induced retinopathy modeling ischemic proliferative retinopathies. Inhibition of SLC38A5 in human retinal vascular ECs impairs EC proliferation and angiogenic function, suppresses glutamine uptake, and dampens vascular endothelial growth factor receptor 2. Together these findings suggest that SLC38A5 is a new metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in ECs.

GLS and GOT2 as prognostic biomarkers associated with dendritic cell and immunotherapy response in breast cancer

“…There was not glutamine metabolism related reports about F13A1, NOS3, GFPT2, TGM2 and SLC7A7 genes. SLC38A5 is reported as a amino acid transporter shuttled amino acids (including glutamine) across cell member but not the glutamine specific transporter [ [55] , [56] , [57] ]. Both GLS and GOT2 were essential genes to glutamine metabolism [ 28 , 36 , 37 ].…”

Efficient fine-tuning of endothelial gene expression by a single Tyrosine to Phenylalanine point mutation in theVE-cadheringene

“…The genes encoding for enzymes involved in membrane co-transport include Scl36a2 ( Solute Carrier Family 36 Member 2), which encodes for an electrogenic proton/amino acid that is involved in transmembrane movement of amino acids and derivatives (47). The gene Scl38a5 encoded for protein that cotransports neutral amino acids and sodium ions, coupled to an H + antiporter activity (48). The gene Scn3a encodes for a voltage-gated sodium channels which are transmembrane glycoprotein complexes (49).…”

Genetic deficiency and pharmacological modulation of RORα regulate laser-induced choroidal neovascularization

“…Cells between passage number 4 and 7 were treated with SR3335, SR1078 (both 10 μM) or vehicle DMSO. Cell viability and/or proliferation was assessed after treatment using an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell metabolic activity assay kit (V13154, Fisher Scientific) as described previously [ 45 ]. Cell migration assay was carried out according to previous protocols [ 46 ].…”