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Attenuation of Neointimal Formation with Netrin‐1 and Netrin‐1 Preconditioned Endothelial Progenitor Cells
Author(s) -
Liu Norika Mengchia,
Siu Kin Lung,
Youn JiYoun,
Cai Hua
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb577
Subject(s) - restenosis , neointima , medicine , progenitor cell , netrin , endothelial progenitor cell , angiogenesis , neointimal hyperplasia , endothelium , cancer research , microbiology and biotechnology , receptor , biology , stem cell , stent , axon guidance
Restenosis after angioplasty is a serious clinical problem that can result in reocclusion of the coronary artery. Although current drug eluting stents have proved to be more effective in reducing restenosis, they have drawbacks of inhibiting reendothelialization to promote thrombosis. New treatment options are in urgent need. We have shown that netrin‐1, an axon‐guiding protein, promotes angiogenesis and cardioprotection via production of nitric oxide (NO). The present study examined whether and how netrin‐1 attenuates neointimal formation in a femoral wire injury model. Infusion of netrin‐1 into C57BL/6 mice via an osmotic minipump markedly attenuated neointimal formation following wire injury of femoral arteries, measured by intimal to media ratio (from 1.94±0.55 to 0.45±0.86 at 4 weeks). This protective effect was absent in DCC +/− animals, which lack netrin‐1 receptor DCC. Vascular smooth muscle cell (VSMC) migration was significantly abrogated by netrin‐1, and this response was mediated by a NO/cGMP/p38 MAPK pathway. Proliferation of VSMC in situ was also largely attenuated by netrin‐1 treatment. Injection of netrin‐1 preconditioned endothelial progenitor cells (EPCs) significantly reduced neointimal formation, which was dependent on DCC presence on EPCs. Netrin‐1 significantly augmented EPC proliferation, NO production, and resistance to oxidative stress, implicating improved function of EPCs to participate in the repair process. In conclusion, these data indicate that netrin‐1 is highly effective in reducing neointimal formation following vascular endothelial injury, which is dependent on DCC, and attributed to inhibition of VSMC proliferation and migration as well as improved EPC function. These data may support usage of netrin‐1 and netrin‐1 preconditioned EPCs as novel therapies for post‐angioplasty restenosis. Support or Funding Information HL077440