LIM Kinase regulation of cofilin activity mediates PDGF‐induced VSMC migration

Abstract

Platelet derived growth factor (PDGF) is a pro‐migratory factor released in response to vascular injury. Vascular smooth muscle cells (VSMCs) mediate this response and contribute significantly to neointimal formation, thus delineating the molecular mechanisms of VSMC migration is critical to understanding the vascular repair process. Signaling cascades activated by PDGF ultimately converge upon the actin cytoskeleton which is a key regulator of migration. Recent studies report that cofilin, which upon activation depolymerizes actin and it's phosphatase Slingshot (SSH) are essential to PDGF‐induced VSMC migration. In addition to SSH, cofilin activity is also regulated by LIM‐kinase, which attenuates its activity. Thus, in these studies we examined the role of LIMK in PDGF‐induced VSMC migration. Immunoblotting with phosphospecific antibodies confirmed that LIMK activity was increased in a time dependent manner in response to PDGF. Transfection of VSMCs cells with LIMK siRNA attenuated PDGF induced migration by 70% vs. control VSMCs. The knockdown of LIMK expression by siRNA also decreased basal phosphorylation of cofilin and potentiated the cofilin response to PDGF‐induced activation. As PDGF‐induced LIMK regulation appears to mediate VSMC migration, these studies show the importance of further examining the SSH/LIMK balance in mediating cytoskeletal events associated with cofilin activity.