BIMODAL EFFECTS OF ANGIOTENSIN-II ON MIGRATION OF HUMAN AND RAT SMOOTH-MUSCLE CELLS - DIRECT STIMULATION AND INDIRECT INHIBITION VIA TRANSFORMING GROWTH-FACTOR-BETA-1

Angiotensin II may be an important mediator of neointima formation in vascular disease. This study was de signed to examine the mechanisms i nvolved in angiotensin II-stimulated migration of human and rat aortic vascular smooth muscle cells (VSMCs). VSMCs were seeded in one corner of Nunc four-well culture chambers; angiotensin II within filter pape r was glued onto the wall of the opposite side. After 48 hours of incu bation in serum-free medium containing growth-arresting factor, migrat ed cells were counted using a light microscope. Angiotensin II (2x10(- 11) to 2x10(-8) mol/L) increased migration of VSMCs in a concentration -dependent manner. Interestingly, at higher concentrations of angioten sin II (up to 2x10(-6) mol/L), migration was reduced to levels compara ble with control levels. Losartan, an AT(1) receptor antagonist, preve nted migration, while PD123319, an AT(2) receptor antagonist, had no s ignificant inhibitory effect Transforming growth factor-beta 1 (TGF-be ta 1; 0.01 to 10.0 pg/mL) inhibited migration induced by angiotensin I I (2x10(-8) mol/L) in a concentration-dependent manner. A neutralizing TGF-beta antibody unmasked migratory effects of high concentrations o f angiotensin II. Furthermore, angiotensin II (10(-6) mol/L) upregulat ed TGF-beta 1 mRNA levels fivefold in rat and fourfold in human VSMCs; this effect was prevented by losartan but not by PD123319. Thus, the effects of angiotensin II on migration of VSMCs are bimodal, ie, both migratory and antimigratory pathways are activated. Autocrine release of TGF-beta 1 induced by angiotensin II exerts an antimigratory effect in rat and human VSMCs. The AT(1) receptor is involved in regulation of both pathways.