PAI-1 and Cellular Migration
Dabbling in Paradox
“Do not dabble in paradox, it puts you in danger of fortuitous wit.”
— T. Stoppard, Arcadia, 1995
The migration of vascular smooth muscle cells (SMCs) plays an important role in the response to vascular injury and in atherosclerosis. In fact, the focal accumulation of smooth muscle in the arterial intima is thought to make a critical contribution to the formation of vascular lesions. Smooth muscle migration is a complex process that requires a stimulus and a matrix substratum that facilitates cell adhesion and movement. Cells attach via specific integrin receptors that bind to the matrix, thereby providing “traction” for cells and the necessary engagement of intercellular micromotors that drive cell movement.
See page 1573
Based on observations originally made in genetically modified mice, a role for plasminogen activator inhibitor-1 (PAI-1) on cellular migration was suggested.1 Urokinase-type plasminogen activator (u-PA)–deficient mice exhibit a reduced neointimal response to injury. In contrast, PAI-1–deficient mice show an exaggerated neointimal response to injury while adenoviral-delivered PAI-1 overexpression inhibits vascular wound healing and neointima formation. Since PAI-1 plays as a direct and fast-acting inhibitor of u-PA, it was argued that these observations could be explained by enhanced matrix degradation and accelerated cell migration in the absence of PAI-1. Subsequently, Stefansson and Lawrence2 showed that active PAI-1 directly impairs SMC adhesion and migration by limiting the binding of vitronectin to the integrin receptor αvβ3. PAI-1 probably also impairs cell adhesion and migration by competitively inhibiting the binding of the u-PA receptor to vitronectin. If the story ended there, the functional effects of PAI-1 on cell migration would be relatively predictable. However, it has now been convincingly demonstrated that PAI-1 can alternatively retard or enhance cell adhesion and migration, depending on the type of cells studied, the experimental conditions, and the conformation of the PAI-1.3–8⇓⇓⇓⇓⇓
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Tanaka and colleagues9 present data indicating that PAI-1 can paradoxically enhance, rather than impair, SMC migration under selective circumstances. The fundamental observation made in this study centers on classical concept that SMC phenotype is strongly influenced by the surface on which the cells are cultured. Cells grown on polymerized collagen type 1 are arrested in a nonsynthetic, G1 phase of the cell cycle.10 While these cells show limited migratory potential when replated on a vitronectin surface, the current studies show that the addition of exogenous PAI-1 restores and enhances platelet-derived growth factor–stimulated SMC migration on vitronectin. Interestingly, PAI-2 failed to restore SMC migratory potential in response to angiotensin II. The authors suggest that these results may be explained by a reduction in the stringency of binding, which in turn allows for greater cellular motility.
While this study suggests that the effects of PAI-1 and SMCs are complex and influenced by cell phenotype and substratum composition, there are clear limitations to the findings and conclusions. The experiments described here, as well as those of previous reports, do not completely recapitulate the complex environment seen by vascular SMCs in vivo in diseased or in injured arterial walls. The composite effect of PAI-1 and vascular smooth muscle migration likely depends on multiple factors, including cellular phenotype, the chemotactic stimulus, and the composition of matrix in which they reside and subsequently migrate. Other factors may also come into play, including the concentration of PAI-1 and its conformation. However, it is evident that under some circumstances, PAI-1 can enhance cellular migration, and this may provide some insights into the mechanisms through which PAI-1 augments the invasiveness of malignant cells and the strong association between PAI-1 and metastasis in breast cancer.11 While further work needs to be done to understand how PAI-1 effects cellular migration and how this interaction can be exploited to prevent or treat human disease, the current study suggests that PAI-1 can play a molecular “Jekyll and Hyde” when it comes to SMC migration.
- ↵Carmeliet P, Moons L, Lijnen R, Janssens S, Lupu F, Collen D, Gerard RD. Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice. Circulation. 1997; 96: 3180–3191.
- ↵Isogai C, Laug WE, Shimada H, Declerck PJ, Stins MF, Durden DL, Erdreich-Epstein A, DeClerck YA. Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. Cancer Res. 2001; 61: 5587–5594.
- ↵Kjoller L, Kanse SM, Kirkegaard T, Rodenburg KW, Ronne E, Goodman SL, Preissner KT, Ossowski L, Andreasen PA. Plasminogen activator inhibitor-1 represses integrin- and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation. Exp Cell Res. 1997; 232: 420–429.
- ↵Tanaka S, Koyama H, Ichii T, Shioi A, Hosoi M, Raines EW, Nishizawa Y. Fibrillar collagen regulation of plasminogen activator inhibitor-1 is involved in altered smooth muscle cell migration. Arterioscler Thromb Vasc Biol. 2002; 22: 1573–1578.
- ↵Koyama H, Tanaka S, Kim S, Shioi A, Okuno Y, Raines EW, Iwao H, Otani S, Nishizawa Y. Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors. Circ Res. 2001; 88: 460–467.