Enhanced pulsatile pressure accelerates vascular smooth muscle migration: implications for atherogenesis of hypertension.
OBJECTIVE
Clinical studies have suggested that pulsatile pressure is an independent risk factor for atherosclerosis. However, it is unknown whether enhanced pulsatile pressure per se directly accelerates vascular smooth muscle cell (VSMC) migration, an important process of atherosclerosis.


RESULTS
Using our original Pressure-loading system with a Boyden chamber, we examined the direct effects of variable pressures and pulse rates on migration of rat aortic VSMCs in vitro. High pulse pressure (180/90 mmHg, pulsatile vs. 180 mmHg, static), high mean pressure (180/90 vs. 90/0 mmHg, with the same pulse pressure), wide pulse pressure (190/110 vs. 170/130 mmHg, with the same mean pressure), and high pulse rate (120 vs. 40 per min) significantly accelerated the VSMC migration (1.35, 2.38, 1.38 and 1.27-fold, respectively). The increase in intracellular calcium levels measured by fura-2/AM fluorescence was proportional to the magnitude of pressure loaded. The pressure-promoted VSMC migration was significantly inhibited by a phospholipase-C inhibitor U-73122 or a calmodulin inhibitor W-7. Inositol 1,4,5-trisphosphate receptor blockers 2-aminoethoxydiphenyl borate or xestospongin-C significantly inhibited the VSMC migration, whereas a ryanodine receptor blocker ryanodine had no effects. Furthermore, a calcium channel blocker (CCB), azelnidipine, and an angiotensin type-1 receptor blocker, olmesartan, also significantly inhibited the VSMC migration.


CONCLUSIONS
These results provide direct evidence for the pro-atherogenic effects of enhanced pulsatile pressure and also suggest that the anti-atherogenic actions of CCBs and angiotensin type-1 receptor blockers are mediated in part by their direct inhibitory effects on VSMC migration in addition to their anti-hypertensive effects.
Tada
Tomohiro
T
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai 980-8574, Japan.
Nawata
Jun
J
Wang
Huan
H
Onoue
Noriko
N
Zhulanqiqige
Doe
D
Ito
Kenta
K
Sugimura
Koichiro
K
Fukumoto
Yoshihiro
Y
Shimokawa
Hiroaki
H
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000503:physiopathology; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology; D004195:Disease Models, Animal; D004864:Equipment and Supplies; D004963:Estrenes / Q000494:pharmacology; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors; D047028:Macrocyclic Compounds / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology*; D010080:Oxazoles / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D047228:Angiotensin II Type 1 Receptor Blockers; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D004963:Estrenes; D007093:Imidazoles; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D011760:Pyrrolidinones; D013777:Tetrazoles; C511704:xestospongin C; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D001383:Azetidinecarboxylic Acid; C437965:olmesartan; D010738:Type C Phospholipases; C061679:azelnidipine