Attenuation of neointimal formation with netrin-1 and netrin-1 preconditioned endothelial progenitor cells

作者：Liu Norika Mengchia; Siu Kin Lung; Youn Ji; Cai Hua^*

来源：Journal of Molecular Medicine-JMM, 2017, 95(3): 335-348.

DOI：10.1007/s00109-016-1490-4

• Netrin-1
• Neointimal formation
• Vascular smooth muscle cell (VSMC) proliferation
• VSMC migration
• Femoral wire injury
• Deleted in colorectal cancer (DCC)
• Endothelial progenitor cells (EPCs)
• EPC proliferation
• Endothelial nitric oxide synthase (eNOS) phosphorylation
• NO production
• EPC resistance to oxidative stress
• EPC homing
• Re-endothelialization

Restenosis after angioplasty is a serious clinical problem that can result in re-occlusion of the coronary artery. Although current drug-eluting stents have proved to be more effective in reducing restenosis, they have drawbacks of inhibiting re-endothelialization 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 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). Proliferation of VSMC in situ was largely reduced. This protective effect was absent in DCC+/- animals. NO production was increased by netrin-1 in both intact and injured femoral arteries, indicating netrin-1 stimulation of endogenous NO production from intact endothelium and remaining endothelial cells post-injury. VSMC migration was abrogated by netrin-1 via a NO/cGMP/p38 MAPK pathway, while timely EPC homing was induced. Injection of netrin-1 preconditioned wild-type EPCs, but not EPCs of DCC+/- animals, substantially attenuated neointimal formation. EPC proliferation, NO production, and resistance to oxidative stress induced apoptosis were augmented by netrin-1 treatment. In conclusion, our data for the first time demonstrate 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.

• 出版日期2017-3