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HMG-CoA reductase inhibitors have direct vascular effects that contribute to plaque stability. In the current study, the authors demonstrate that the HMG-CoA reductase inhibitors atorvastatin and pravastatin augment the adhesion of human (HSMCs) and rat aortic smooth muscle cells (RASMCs) to collagen I via induction of 21-integrin receptors. Atorvastatin (0.1 M) increased the adhesion of HSMCs to collagen I up to 2-fold (p < 0.01) and pravastatin (1.0 M) up to 1.8-fold (p < 0.01) after treatment of at least 24 h. This increase in adhesion was concentration dependent and was observed for treatment periods from 16 to 72 h. Inhibition of isoprenoid synthesis with mevalonate and geranyl-geraniol prevented the statin-induced effect on human and rat smooth muscle cells. Flow cytometry revealed an increased expression of 2- and 1-integrins after treatment with atorvastatin (0.1 M) at 24 and 48 h. Atorvastatin increased levels of 1-integrin mRNA after 12- and 24-h treatment in HSMCs, which was inhibited by mevalonate. Furthermore, atorvastatin (0.1 M) and pravastatin (1.0 M) inhibited chemotaxis of HSMCs on collagen I, which was also reversed by mevalonate treatment. In contrast, inhibition of 1-integrins with a specific antibody nearly doubled (p < 0.01) the rate of chemotaxis. These data indicate that the chemotactic activity in HSMCs is inhibited in part by up-regulation of 21-integrin receptors. The current study indicates that HMG-CoA reductase inhibitors increase cell–matrix interaction with collagen I via induction of 21-integrins and increased adhesion to collagen I.

Vascular smooth muscle cell (VSMC) migration involves adhesion, locomotion, and invasion regulated by various signaling molecules, among which the extracellular signal–regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) play a critical role. We have shown that the peroxisome proliferator-activated receptor- (PPAR-) ligands troglitazone and rosiglitazone inhibit VSMC migration downstream of ERK MAPK. The purpose of the current study was to more specifically determine which step(s) in VSMC migration are targeted by inhibition of the ERK MAPK pathway or activation of PPAR-. VSMC adhesion was not affected by the ERK MAPK pathway inhibitor PD98059 or PPAR- ligands. Phosphorylation and activation of myosin light chain kinase (MLCK) play important roles in cell locomotion. Platelet-derived growth factor (PDGF)-induced MLCK phosphorylation (1.7-fold) was completely blocked by PD98059 at 30 M(p < 0.05), but not by troglitazone or rosiglitazone. PDGF-directed migration (5.8-fold) was inhibited by PD98059 (−88 at 30 M) and the MLCK inhibitor ML9 (0.1–1 M, −84 at 1 M) (all p < 0.05). The transcription factor Ets-1 mediates matrix metalloproteinase induction required for tissue invasion by VSMC. PDGF (20 ng/ml) stimulated an Ets-1 protein expression (14-fold at 60 min) in VSMC, which was inhibited by PD98059 (−72 at 30 M), troglitazone (−69 at 20 M), and rosiglitazone (−54 at 10 M) (all p < 0.05). Immunohistochemistry of rat aortae 2 h after balloon injury showed a dramatic upregulation of Ets-1, which was markedly inhibited in animals that had received troglitazone treatment. In contrast, phosphorylated ERK MAPK was not affected by troglitazone. These data are consistent with PPAR- ligands exerting their anti-migratory effects downstream of ERK MAPK activation by blocking nuclear events, such as Ets-1 expression, required for cell invasion in response to arterial injury.