Syndecan-4 deficiency limits neointimal formation after vascular injury by regulating vascular smooth muscle cell proliferation and vascular progenitor cell mobilization

Objective- Syndecan-4 (Syn4) is a heparan sulfate proteoglycan and works as a coreceptor for various growth factors. We examined whether Syn4^-/- could be involved in the development of neointimal formation in vivo. Methods and Results- Wild-type (WT) and Syn4^-/--deficient (Syn4 ^-/-) mice were subjected to wire-induced femoral artery injury. Syn4^-/- mRNA was upregulated after vascular injury in WT mice. Neointimal formation was attenuated in Syn4^-/- mice, concomitantly with the reduction of Ki67-positive vascular smooth muscle cells (VSMCs). Basic-fibroblast growth factor- or platelet-derived growth factor-BB-induced proliferation, extracellular signal-regulated kinase activation, and expression of cyclin D1 and Bcl-2 were impaired in VSMCs from Syn4^-/- mice. To examine the role of Syn4^-/- in bone marrow (BM)-derived vascular progenitor cells (VPCs) and vascular walls, we generated chimeric mice by replacing the BM cells of WT and Syn4^-/- mice with those of WT or Syn4^-/- mice. Syn4^-/- expressed by both vascular walls and VPCs contributed to the neointimal formation after vascular injury. Although the numbers of VPCs were compatible between WT and Syn4^-/- mice, mobilization of VPCs from BM after vascular injury was defective in Syn4 ^-/- mice. Conclusion- Syn4^-/- deficiency limits neointimal formation after vascular injury by regulating VSMC proliferation and VPC mobilization. Therefore, Syn4^-/- may be a novel therapeutic target for preventing arterial restenosis after angioplasty.