Increased static pressure promotes migration of vascular smooth muscle cells: involvement of the Rho-kinase pathway.
Vascular smooth muscle cell (VSMC) migration plays a pivotal role in the pathogenesis of arteriosclerosis, under influences of various mechanical factors. Thus, we examined whether static pressure promotes VSMC migration and if so, whether Rho-kinase is involved. Rat VSMCs were cultured on chambers coated on fibronectin, vitronectin, laminin, or type IV collagen, under pressure-free conditions and at 90 and 180 mm Hg. In monolayer-wounding assay, VSMC migration was significantly increased after 72 hours at 180 mm Hg on both fibronectin (11.3 +/- 3.4-fold vs. pressure-free conditions) and vitronectin (10.6 +/- 0.7-fold; both P < 0.05). In Boyden chamber assay, the VSMC migration was again significantly increased at 180 mm Hg on both fibronectin (4.0 +/- 0.5-fold) and vitronectin (5.0 +/- 0.8-fold; both P < 0.05). Neutralizing antibodies against beta1-, beta3- and beta5-integrins, all of which play an important role in cell migration, significantly inhibited the pressure-promoted VSMC migration. Static pressure also significantly increased Rho-kinase activity in VSMC, as evaluated by the extent of phosphorylation of its downstream substrate, ezrin-radixin-moesin. Fasudil, a selective Rho-kinase inhibitor, significantly suppressed the pressure-promoted VSMC migration with reduced Rho-kinase activity. These results indicate that increased static pressure promotes VSMC migration through the integrin/Rho-kinase signaling, suggesting the therapeutic importance of this mechanism for the treatment of hypertensive vascular diseases.
Onoue
Noriko
N
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Nawata
Jun
J
Tada
Tomohiro
T
Zhulanqiqige
Doe
D
Wang
Huan
H
Sugimura
Koichiro
K
Fukumoto
Yoshihiro
Y
Shirato
Kunio
K
Shimokawa
Hiroaki
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D066298:In Vitro Techniques; D039641:Integrin beta Chains / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011312:Pressure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000378:metabolism*
D000906:Antibodies; D039641:Integrin beta Chains; D019012:Integrin beta1; D039661:Integrin beta3; D047428:Protein Kinase Inhibitors; C084344:integrin beta5; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil