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

WILLIAM DURANTE^*,1, LAN LIAO^*, SYLVIA V. REYNA^*, KELLY J. PEYTON^* and ANDREW I. SCHAFER^*

^* Houston VA Medical Center and the Departments of Medicine; and
Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA

¹Correspondence: Houston VA Medical Center, Bldg. 109, Room 130, 2002 Holcombe Blvd., Houston TX 77030, USA. E-mail:wdurante{at}bcm.tmc.edu

Application of cyclic stretch (10% at 1 hertz) to vascular smooth muscle cells (SMC) increased L-arginine uptake and this was associated with a specific increase in cationic amino acid transporter-2 (CAT-2) mRNA. In addition, cyclic stretch stimulated L-arginine metabolism by inducing arginase I mRNA and arginase activity. In contrast, cyclic stretch inhibited the catabolism of L-arginine to nitric oxide (NO) by blocking inducible NO synthase expression. 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 reversed by methyl-L-arginine, a competitive inhibitor of L-arginine transport, by hydroxy-L-arginine, an arginase inhibitor, or by the ornithine aminotransferase inhibitor L-canaline. Finally, cyclic stretch stimulated collagen synthesis and the accumulation of type I collagen, which was inhibited by L-canaline. These results demonstrate that cyclic stretch coordinately stimulates L-proline synthesis by regulating the genes that modulate the transport and metabolism of L-arginine. In addition, they show that stretch-stimulated collagen production is dependent on L-proline formation. The ability 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.—Durante, W., Liao, L., Reyna, S. V., Peyton, K. J., Schafer, A. I. Physiological cyclic stretch directs L-arginine transport and metabolism to collagen synthesis in vascular smooth muscle.

Key Words: biomechanical strain • L-proline • cationic amino acid transporter • arginase • vascular cells

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