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.
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.
Authors: Trisha R Stankiewicz; Sai Anandi Ramaswami; Ron J Bouchard; Klaus Aktories; Daniel A Linseman Journal: J Biol Chem Date: 2015-02-09 Impact factor: 5.157
Authors: Ming Liang; Lauren E Woodard; Anlin Liang; Jinlong Luo; Matthew H Wilson; William E Mitch; Jizhong Cheng Journal: Am J Pathol Date: 2015-03-14 Impact factor: 4.307
Authors: Ming Liang; Qunying Guo; Fengzhang Huang; Guofeng Han; Ke Song; Jinlong Luo; Hunter Cheng; Hongzhen Hu; Eric K Peden; Changyi Chen; William E Mitch; Jie Du; Xiaodong Fu; Luan Truong; Jizhong Cheng Journal: Kidney Int Date: 2019-02-21 Impact factor: 10.612
Authors: Margreet R de Vries; Karin H Simons; J Wouter Jukema; Jerry Braun; Paul H A Quax Journal: Nat Rev Cardiol Date: 2016-05-19 Impact factor: 32.419