Role of Vessel Wall and Bone Marrow Syndecan-4 in Neointimal Hyperplasia

Abstract

S yndecan 4 (Syn4) is 1 of a family of 4 transmembrane heparan sulfate proteoglycans found in mammals. An evolutionary conserved cytoplasmic domain on syndecans supports a key role for cell surface ligand binding and cytoplasmic signaling. Along with integrins, syndecans serve as key structural elements in concentrating ligands on the cell surface. To date, a multiplicity of functions have been ascribed to syndecans, including growth factor tethering in the extracellular matrix (ECM) and cytoplasmic signaling, which activates focal adhesion, cytoskeletal reorganization, and metalloproteinase activation. 1 Syndecans have previously been noted for their ECM sensing and thrombin binding properties in the context of tissue injury and repair, and they perform a key role in regulating basic fibroblast growth factor and platelet-derived growth factor-induced smooth muscle cell (SMC) signaling events supporting activation and regulation of SMC responses to vascular injury. 2,3 See accompanying article on page 1066The study by Ikesue et al 4 in this issue highlights an additional intriguing role for Syn4 that may extend beyond the local vessel wall in the context of injury to bone marrow (BM)-derived cells involved in SMC driven tissue repair. These data are important as they underscore what a number of other recent studies 5,6 have hinted at, namely, a complex interplay among vessel wall cell surface molecules, ECMbound factors, and cells resident in BM during the vascular response to injury. Moreover, although controversy still exists on the precise role of BM cells in SMC differentiation and proliferation following injury, Ikesue et al's study 4 provides supportive evidence for a functional role of BMderived Syn4 in promoting neointimal hyperplasia and vascular progenitor cell (VPC) mobilization.Following balloon angioplasty or stenting, a number of early events occur that may affect cell surface -and matrixbound Syn4, including protease activation in blood and at the site of injury and subsequent cleavage of proteoglycans in the ECM, releasing growth factors such as platelet-derived growth factor and basic fibroblast growth factor, both of which may act as chemotactic and mitogenic factors for SMC within the media and intima of the injured vessel. Ikesue et al's study 4 demonstrates that Syn4 deficiency abrogates basic fibroblast growth factor-protein kinase C signaling and basic fibroblast growth factor/platelet-derived growth factor-BBinduced Erk signal activation with attenuation of SMC proliferation postinjury. It is likely that vitiation of local autocrine and paracrine growth factor pathways is a significant mechanism underlying the reduction in neointima formation. However, intriguingly, this study also shows that BM transplantation of Syn4-deficient marrow into wild-type mice similarly attenuates neointima formation compared with wild-type BM transplantation into Syn4-deficient animals, suggesting that BM Syn4 is also required for neointima formation. Although this study does not clarify precisely what cells ...