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. (Arterioscler Thromb Vasc Biol. 2011;31:1066-1074.)