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 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
W
Houston VA Medical Center and the Departments of Medicine. Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA. wdurante@bcm.tmc.edu
Liao
L
L
Reyna
S V
SV
Peyton
K J
KJ
Schafer
A I
AI
D026923:Amino Acid Transport Systems, Basic; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D002374:Catalase / Q000096:biosynthesis; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D051381:Rats
D026923:Amino Acid Transport Systems, Basic; D011073:Polyamines; C490274:Slc7a2 protein, rat; D003094:Collagen; D001120:Arginine; D011392:Proline; D002374:Catalase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D009955:Ornithine Decarboxylase