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Felix Yemanyi, Zhongxiao Wang, Shuo Huang, Chi-Hsiu Liu, Yohei Tomita, Alexandra K. Blomfield, Zhongjie Fu, Jing Chen; Amino acid transporter SLC38A5 modulates pathological retinal neovascularization in mice. Invest. Ophthalmol. Vis. Sci. 2021;62(8):3182.
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© ARVO (1962-2015); The Authors (2016-present)
Pathological ocular neovascularization (NV) frequently results in vision loss and may be influenced by aberrant transport and metabolism of nutrients like amino acids in vascular endothelial cells (EC). Solute carrier (SLC) transporters are responsible for nutrient and metabolic sensing including amino acid transport. Dysregulation of key subfamilies of SLC transporters has been implicated in many metabolic and vascular diseases including neurovascular eye disorders. Here, we determined the specific role of SLC family 38 member 5 (SLC38A5) in pathological retinal NV using a mouse model of oxygen-induced retinopathy (OIR).
Neonatal C57BL/6J mice were exposed to 75% oxygen from postnatal day (P) 7 to P12 to induce OIR with pathological NV. Slc38a5 mRNA and protein expression levels were determined in OIR or room air control retinas (n=6/group) and laser capture microdissected retinal blood vessels (n=4/group). OIR was induced in Slc38a5 knockout (Slc38a5-/-) and wild type (WT) control mice (n=5/group) and pathological retinal NV and vaso-obliteration (VO) were evaluated at P17. The effect of Slc38a5 deficiency on developmental retinal angiogenesis was analyzed in Slc38a5-/- and WT mice (n=5/group) at P5 and P10. Glutamine uptake and expression of relevant angiogenic regulators were analyzed in human retinal microvascular ECs (HRMECs; n=3) transfected with siRNA targeting SLC38A5 (si-SLC38A5) or control SiRNA (si-Ctrl).
Slc38a5 mRNA or protein levels were substantially upregulated (p<0.01) in P17 OIR whole retinas relative to normoxic control mice, and specifically enriched in pathological NV. Compared with WT controls, genetic deficiency of Slc38a5 significantly attenuated (p<0.01) pathological NV in OIR retinas without markedly affecting VO. Moreover, knockout of Slc38a5 significantly delayed (p<0.01) developmental angiogenesis in P5 and P10 retinas relative to WT. Compared with si-Ctrl, si-SLC38A5 transfected HRMECs exhibited profound decrease in glutamine uptake associated with downregulation of crucial angiogenic factors and their receptors (IGF2, ANG1 and 2, FGF2, VEGFR1 and 2, IGFR, FGFR2 and 3, TIE2).
These data show that SLC38A5 regulates pathological retinal NV potentially via controlling glutamine uptake and angiogenic regulators in vascular ECs. Thus, targeting SLC38A5 may aid the design of novel therapeutics to ameliorate pathological NV in vascular eye diseases.
This is a 2021 ARVO Annual Meeting abstract.
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