Abstract 16219: Effects of Netrin-1 on Vascular Injury and Repair
Post-angioplasty restenosis is a major complication after angioplasty surgery. While several strategies exist to limit this phenomenon, they each have their own shortcomings. In this work, we tested whether netrin-1, which we have shown previously to be a powerful angiogenic and cardioprotective agent via production of nitric oxide (NO), can be used to prevent the typical phenotypes of restenosis using the femoral wire injury mice model. Animals were infused with either vehicle or netrin-1 (15 ng/day) via an osmotic pump for 14 days with the netrin-1 grouped started 2 days prior. On the second day, femoral artery injury was performed by passing a guide wire inside of the right femoral artery 3 times, each time held for 30 seconds. The artery was then ligated and checked for blood flow before closure of the wound site. Sham surgery was performed on the left femoral artery. Femoral arteries were harvested 12 days after the surgery, fixed in paraffin, and sectioned in paraffin. Visualization of the vessels using H & E and trichrome staining reveals neointimal formation when compared to uninjured controls, which was abolished in netrin-1 treated animals. This effect of netrin-1 was not observed in DCC+/- animals, which are deficient in the receptor for netrin-1. In additional experiments we found that netrin-1 potently and dose-dependently inhibited vascular smooth muscle cell (VSMC) migration and proliferation, which are hallmarks of neointimal formation and restenosis. These responses were also inhibited by pre-incubation of the cells with DCC-antibody. It has been shown that endothelial progenitor cells (EPCs) play an important in vascular repair. In parallel experiments we found that pre-treatment of bone marrow-derived EPCs with netrin-1 markedly attenuated hydrogen peroxide induced EPC apoptosis (14% dead cells from 45% in untreated group). In summary, netrin-1 appears to inhibit vascular injury and promote vascular repair via attenuation of VSMC migration and proliferation, as well as promotion of EPC survival, resulting in reduced neointimal formation and likely restenosis. These data represent the fist evidence that netrin-1 can be used as a powerful protector against vascular injury.
- © 2011 by American Heart Association, Inc.