Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis.
Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis.
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作者：
Wang Z;Yemanyi F;Blomfield AK;Bora K;Huang S;Liu CH;Britton WR;Cho SS;Tomita Y;Fu Z;Ma JX;Li WH;Chen J
血管内皮细胞的氨基酸代谢对出芽性血管生成具有重要作用。SLC 38 A5（溶质载体家族38成员5）是一种AA转运蛋白，其穿梭中性AA穿过细胞膜，包括谷氨酰胺，其可充当增殖内皮细胞（EC）的代谢燃料以促进血管生成。在这里，我们发现Slc 38 a5在正常视网膜血管内皮中高度富集，更具体地说，在病理性出芽新生血管中高度富集。Slc 38 a5在Lrp 5 −/−和Ndpy/−小鼠的视网膜血管中受到抑制，这两种小鼠都是Wnt信号突变导致视网膜血管发育缺陷的遗传模型。此外，Slc 38 a5转录受Wnt/β-catenin信号传导调节。小鼠中Slc 38 a5的遗传缺陷显著延迟视网膜血管发育并抑制氧诱导的视网膜病模型缺血性增殖性视网膜病中的病理性新血管形成。在人视网膜血管EC中抑制SLC 38 A5损害EC增殖和血管生成功能，抑制谷氨酰胺摄取，并抑制血管内皮生长因子受体2。总之，这些发现表明SLC 38 A5是通过控制EC中AA营养摄取和体内平衡的视网膜血管生成的新代谢调节剂。
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.