Regulation of arterial lesions in mice depends on differential smooth muscle cell migration: A role for sphingosine-1-phosphate receptors

The response of mice arteries to injury varies significantly between strains. FVB mice develop large neointimas after injury, whereas very small lesions form in C57BL/6 mice. After injury, platelet interaction with the denuded artery and early smooth muscle (SMC) replication are identical in both strains; however, the migration of SMCs differs significantly. FVB cells readily move into the developing neointima, whereas only the occasional C57BL/6 cells migrate. Injured arteries showed no difference in matrix metalloproteinases (MMP-2 and MMP-9) and plasminogen activator activities. In vitro, sphingosine-1-phosphate (S1P) in combination with platelet-derived growth factor (PDGF) stimulates migration of FVB cells but inhibits migration of C57BL/6 SMCs. Both SMCs migrate equally well to PDGF alone. One explanation is that the SMCs express different S1P receptors. Real-time polymerase chain reaction shows that FVB cells express higher levels of S1P receptor-1 (S1P1) compared with C57BL/6 cells, which express higher levels of S1P receptor-2 (S1P2). In addition, the migration of C57BL/6 cells can be increased by inhibiting S1P2, whereas inhibiting S1P1 expression slows the migration of FVB cells. Taken together these studies suggest that expression of S1P receptors vary within inbred mouse strains and that S1P is critical for SMC migration and lesion formation after injury.

Clinical RelevanceThis report shows that the arteries of C57BL/6 and FVB mice vary in their ability to develop arterial neointimal lesions after injury. A major difference relates to ability of FVB smooth muscle cells to migrate into the intima and so develop neointimal lesions. In vitro FVB cells migrate well in response to sphingosine 1-phosphate (a component of plasma) but C57BL/6 cells do not. FVB cells express sphingosine-1-phosphate (S1P1) and low levels of S1P2 receptors, whereas C57BL/6 cells show higher S1P2 expression. These data suggest that differences in S1P receptor expression are important role in the formation of neointimal lesions.