LAT1 Promotes Angiogenic Responses in Human Endothelial Cells

Abstract

L‐type amino acid transporter 1 (LAT1) is a sodium‐independent high‐affinity transporter of large neutral amino acids, such as L‐leucine. LAT1 is abundantly expressed in a wide range of tumor cells but displays a more restricted pattern of expression in non‐transformed cells. We previously reported that LAT‐1 is present in vascular smooth muscle cells and that it plays a fundamental role in cell proliferation and survival. Since vascular endothelium also expresses LAT1, the present study investigated the functional activity and significance of this transporter in cultured human umbilical vein endothelial cells (ECs). We found that the transport of radiolabeled‐leucine by ECs was time‐dependent and linear for up to 5 minutes. The endothelial uptake of leucine was not dependent on sodium or pH, and was strongly inhibited by neutral, but not basic or acidic amino acids. Leucine transport was also abolished by the selective inhibitor of system L transport, 2‐amino‐2‐norbornanecarboxylic acid (BCH). Interestingly, blockade of leucine transport by BCH was associated with a striking concentration‐ and time‐dependent decrease in EC proliferation and DNA synthesis. Cell cycle analysis found that BCH arrested ECs in the G0/G1 phase of the cell cycle. Furthermore, EC migration following scrape injury was significantly attenuated by BCH. Moreover, the formation of endothelial tubes following the plating of ECs onto matrigel was markedly reduced by BCH. Finally, ex vivo treatment of mouse aortic rings with BCH diminished EC sprouting from these rings. In conclusion, this study demonstrates that ECs exhibit LAT1 activity, and that LAT1 plays an essential role in stimulating EC proliferation, migration, and tube formation. In addition, it identifies LAT1 as an attractive therapeutic target in treating angiogenesis‐dependent disease.Support or Funding InformationSupported by the NIH Grant HL‐59976.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.