This proposal is directed at testing the hypothesis that a mammalian -galactoside-binding lectin, galectin-1, can regulate migration of vascular smooth muscle cells (VSMC) through its specific affinity for integrin receptors. Better understanding of VSMC migration is critical for treating such major human diseases as atherosclerosis, angioplasty restenosis, and graft arteriopathy. VSMC are normally non-motile, but in these diseases they become activated to migrate toward the lumen forming neointimal mounds which occlude blood flow. One function of galectin-1 may be to help restrict VSMC migration. We have found that: 1) Galectin-1 is normally expressed at high levels in extracellular matrix surroundings VSMC, but is greatly decreased after angioplasty. 2) Galectin-1 added to VSMC in culture almost completely inhibits cell migration. 3) Galectin-1 specifically binds to members of the integrin family of receptors, cell surface glycoproteins which mediate many responses to extracellular matrix, including cell adhesion and migration. Therefore, it seems likely that galectin-1 inhibition results from its binding to these receptors, though the precise mechanisms remain unclear. Galectin-1 does not totally block integrin function; only inhibiting VSMC migration without affecting adhesion. Crosslinking of integrins can transduce a range of intracellular signals. It is hypothesized that crosslinking induced by the divalent lectin affects signals required for migration. Preliminary studies that galectin-1 stimulates phosphorylation of focal adhesion kinase (FAK), a signaling protein implicated in integrin-mediated cell migration.
The specific aims are to: 1) finish identifying which VSMC integrins are bound by galectin-1. 2) test the influence of galectin-1 on VSMC integrin localization and cytoskeletal organization, and 3) test the influence of galectin-1 on phosphorylation signals regulating migration. These studies should add significantly to the understanding of both galectin-1 function and VSMC migration and could lead to novel approaches for preventing and treating vascular disease.
| Cooper, D N; Barondes, S H (1999) God must love galectins;he made so many of them. Glycobiology 9:979-84 |
