FSP-1 silencing in bone marrow cells suppresses neointima formation in vein graft

Circ Res. 2012 Jan 20;110(2):230-40. doi: 10.1161/CIRCRESAHA.111.246025. Epub 2011 Nov 23.


Rationale: Fibroblast-specific protein 1 (FSP-1) plays multiple roles in promoting cell proliferation and motility. Increased FSP-1 expression in smooth muscle cells (SMCs) has been associated with their enhanced proliferation.

Objective: To study how FSP-1 contributes to neointima formation of vein grafts.

Methods: Arteriovenous grafts were created in wild-type or FSP-1-GFP mice (green fluorescent protein expression regulated by FSP-1 promoter). The effects of FSP-1 on bone marrow (BM) cell migration and on SMC proliferation were studied in vivo and in vitro.

Results: On creation of a vein graft, there was rapid deposition of platelets on the denuded surface leading to secretion of the chemokine stromal cell-derived factor-1α (SDF-1α). This was followed by recruitment of BM-derived cells expressing the SDF-1α receptor CXCR4; homing of FSP-1-positive cells was found to be dependent on platelet-derived SDF-1α. FSP-1 was expressed in 8% of the BM cells, and 20% of these express CD45; 85% of FSP-1-positive cells express CD11b. We found that the FSP-1-positive cells migrated into the vein graft in a Rac-1-dependent fashion. FSP-1 expression was also found to stimulate proliferation of SMCs through a MEK5-ERK5 signaling pathway that can be suppressed by a dominant-negative Rac1. Consequently, knocking down FSP-1 expression in BM cells prevented neointimal formation.

Conclusions: BM-derived FSP-1(+) cells enhance neointima formation through an increase in transendothelial invasion with stimulation of SMC proliferation. The Rac1 and ERK5 signaling cascade mediate FSP-1-induced responses in SMCs and BM cells. This novel pathophysiology suggests a new therapeutic target, FSP-1, for preventing the development of neointima in vein grafts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Platelets / metabolism
  • Bone Marrow Cells / metabolism*
  • Bone Marrow Transplantation
  • Cell Proliferation*
  • Cells, Cultured
  • Chemokine CXCL12 / metabolism
  • Coculture Techniques
  • Genetic Therapy*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hyperplasia
  • Inflammation Mediators / metabolism
  • MAP Kinase Kinase 5 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 7 / metabolism
  • Neuropeptides / metabolism
  • Promoter Regions, Genetic
  • RNA Interference
  • Recombinant Fusion Proteins / metabolism
  • S100 Calcium-Binding Protein A4
  • S100 Proteins / genetics
  • S100 Proteins / metabolism*
  • Signal Transduction
  • Transendothelial and Transepithelial Migration
  • Tunica Intima / metabolism
  • Tunica Intima / pathology
  • Tunica Intima / transplantation*
  • Vascular Grafting*
  • Vena Cava, Inferior / metabolism
  • Vena Cava, Inferior / pathology
  • Vena Cava, Inferior / transplantation*
  • rac GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein


  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Inflammation Mediators
  • Neuropeptides
  • Rac1 protein, mouse
  • Recombinant Fusion Proteins
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • S100a4 protein, mouse
  • Green Fluorescent Proteins
  • Mitogen-Activated Protein Kinase 7
  • MAP Kinase Kinase 5
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein