TRANSFORMING GROWTH-FACTOR BETA(1) INHIBITS FETAL LAMB DUCTUS-ARTERIOSUS SMOOTH-MUSCLE CELL-MIGRATION

Anatomical closure of the ductus arteriosus (DA) requires normally quiescent smooth muscle cells (SMC) to migrate out of the muscle media into the subendothelial space, forming intimal mounds that eventually coalesce to occlude the vessel's lumen. Transforming growth factor-beta(1) (TGF beta(1)), a potent modulator of vascular SMC migration, is found in the wall of the closing DA. We examined the effect of TGF beta(1) on the migration of fetal lamb DA-SMC. Although TGF beta(1) has been shown to be a chemoattractant for other mesenchymal cells, it had no chemotactic effect on DA-SMC; furthermore, TGF beta(1) did not enhance the migration of DA-SMC (as has been reported for aortic SMC). Rather, incubating DA-SMC with TGF beta(1) for 22 h decreased the rate of migration of SMC on extracellular matrix substrata composed of fibronectin, vitronectin, laminin, and collagen I and IV. Exposure of DA-SMC to TGF beta(1) was associated with an increase in the formation of focal adhesion plaques (tight associations between the cells' surface and extracellular matrix). DA-SMC use integrin receptors to attach to and migrate on extracellular matrix components. The decrease in DA-SMC migration was not associated with a significant change in the profile of integrin receptors expressed by the cell. TGF beta(1) had little effect on overall DA-SMC integrin expression, except for a modest increase in the fibronectin receptor (alpha(5)-beta(1) integrin). Rather, the decrease in migration and changes in cell morphology were associated with an increased ability of integrin receptors to associate with the cytoskeleton. TGF beta(1) appears to anchor the cell's cytoskeleton to the extracellular matrix, making the cells more adherent and less capable of migrating.