Platelet-derived growth factor stimulates LAT1 gene expression in vascular smooth muscle: role in cell growth

Platelet-derived growth factor (PDGF) contributes to vascular disease by stimulating the growth of vascular smooth muscle cells (SMCs). Since amino acids are required for cell growth, the present study examined the effect of PDGF on system L amino acid transport, which is the predominant cellular pathway for the uptake of essential amino acids. System L amino acid transport was monitored by measuring the uptake of L-leucine. Treatment of SMCs with PDGF stimulated L-leucine transport in a concentration- and time-dependent manner, and this was associated with a selective increase in LAT1 mRNA and protein. PDGF failed to induce the expression of the other system L transport proteins, LAT2 and the heavy chain of the 4F2 cell surface antigen. The induction of LAT1 by PDGF was dependent on de novo RNA and protein synthesis and on mTOR activity. Serum, thrombin, and angiotensin II likewise stimulated L-leucine transport by inducing LAT1 expression. Inhibition of system L amino acid transport by the model substrate 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid blocked growth factor-mediated SMC proliferation and induced SMC apoptosis, whereas it had no effect on quiescent cells. These results demonstrate that growth factors stimulate system L amino acid transport by inducing LAT1 gene expression and that system L amino acid transport is essential for SMC proliferation and survival. The capacity of vascular mitogens to induce LAT1 expression may represent a basic mechanism by which tho acid transport * apoptosis