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 designed to examine the mechanisms involved 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 paper was glued onto the wall of the opposite side. After 48 hours of incubation in serum-free medium containing growth-arresting factor, migrated cells were counted using a light microscope. Angiotensin II (2 x 10(-11) to 2 x 10(-8) mol/L) increased migration of VSMCs in a concentration-dependent manner. Interestingly, at higher concentrations of angiotensin II (up to 2 x 10(-6) mol/L), migration was reduced to levels comparable with control levels. Losartan, an AT1 receptor antagonist, prevented migration, while PD123319, an AT2 receptor antagonist, had no significant inhibitory effect. Transforming growth factor-beta 1 (TGF-beta 1; 0.01 to 10.0 pg/mL) inhibited migration induced by angiotensin II (2 x 10(-8) mol/L) in a concentration-dependent manner. A neutralizing TGF-beta antibody unmasked migratory effects of high concentrations of angiotensin II. Furthermore, angiotensin II (10(-6) mol/L) upregulated 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 AT1 receptor is involved in regulation of both pathways.
Liu
G
G
Division of Cardiology, Cardiovascular Research, University Hospital/Inselspital, Bern, Switzerland.
Espinosa
E
E
Oemar
B S
BS
Lüscher
T F
TF
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; C073402:PD 123319; D019808:Losartan