Physiological cyclic stretch directs L-arginine transport and metabolism to collagen synthesis in vascular smooth muscle

Application of cyclic stretch (10% at 1 hertz) to vascular smooth muscle ce lls (SMC) increased L-arginine uptake and this was associated with a specif ic increase in cationic amino acid transporter-2 (CAT-2) mRNA. In addition, cyclic stretch stimulated L-arginine metabolism by inducing arginase I mRN A and arginase activity. In contrast, cyclic stretch inhibited the cataboli sm of L-arginine to nitric oxide (NO) by blocking inducible NO synthase exp ression. Exposure of SMC to cyclic stretch markedly increased the capacity of SMC to generate L-proline from L-arginine while inhibiting the formation of polyamines. The stretch-mediated increase in L-proline production was r eversed by methyl-L-arginine, a competitive inhibitor of L-arginine transpo rt, by hydroxy-L-arginine, an arginase inhibitor, or by the ornithine amino transferase inhibitor L-canaline. Finally, cyclic stretch stimulated collag en synthesis and the accumulation of type I collagen, which was inhibited b y L-canaline. These results demonstrate that cyclic stretch coordinately st imulates L-proline synthesis by regulating the genes that modulate the tran sport and metabolism of L-arginine. In addition, they show that stretch-sti mulated collagen production is dependent on L-proline formation. The abilit y of hemodynamic forces to up-regulate L-arginine transport and direct its metabolism to L-proline may play an important role in stabilizing vascular lesions by promoting SMC collagen synthesis.