Abstract 200: Vascular Stem Cell Migration in Response to Monocyte Chemoattractant Protein-1 Promotes Neointima Lesion Formation
Introduction: While vascular smooth muscle cells are traditionally known for their role in neointima formation, recent studies show that a population of Sca-1+ stem/progenitor cells within the adventitia of vessel walls can also contribute to restenosis formation. To date, their migratory properties and motility in response to fundamental micro-environmental stimuli within the vasculature remain unknown. The occurrence of adventitial inflammation in injured vessels or during atherosclerosis is known to mount an increased secretion of the chemokine, monocyte chemoattractant protein-1 (MCP-1), by cells such as macrophages, endothelial and smooth muscle cells.
Hypothesis: We hypothesize that the MCP-1 plays an important role on the mobilization of vascular progenitor cells.
Methods and Results: Vascular progenitor cells were derived from vein graft and isolated with an anti-Sca-1 antibody microbead system. Using transwell assays, we found that recombinant MCP-1 significantly increased progenitor cell migration. The knockdown of its receptor expression, CCR2, using lentiviral shRNA significantly inhibited MCP-1 induced migration. Mechanistically, cytoskeleton related GTPase rac1 and cdc42 in progenitor cells were activated (in the GTP-bound state) by MCP-1. Furthermore, we showed that the ERK 1/2 pathway was also involved in MCP-1-mediated migration. Consistently, the migration of progenitor cells was significantly decreased following treatment with a MAPKK inhibitor. Using a femoral artery wire injury mouse model, we found that the seeding of Sca-1+ progenitors on the outer layers of the adventitia markedly enhanced neointima formation after 1 week, whereas vessels without progenitor cell seeding did not form neointima. Neointima formation in Sca-1+ progenitors-seeded vessels were found inhibited in mice that lacked functional MCP-1 (n≥8 per group).
Conclusion: In conclusion, MCP-1 can induce adventitia-derived Sca-1+ progenitor cell migration by the activation of GTP-rac1/cdc42 and ERK 1/2 signalling pathway via CCR2. The lack of functional MCP-1 inhibited progenitor cell migration and neointima formation in vivo.
Author Disclosures: B. Yu: None. M.M. Wong: None. W. Wang: None. Y. Hu: None. Q. Xu: None.
- © 2015 by American Heart Association, Inc.