Inhibition of Patched-1 Prevents Injury-Induced Neointimal Hyperplasia
Objective—To determine the role of patched receptor (Ptc)-1 in mediating pulsatile flow-induced changes in vascular smooth muscle cell growth and vascular remodeling.
Approach and Results—In vitro, HCASMC were exposed to normal or pathological low pulsatile flow conditions for 24 hours using a perfused transcapillary flow system. Low pulsatile flow increased vascular smooth muscle cell proliferation when compared with normal flow conditions. Inhibition of Ptc-1 by cyclopamine attenuated low flow-induced increases in Notch expression, whereas concomitantly decreasing HCASMC growth to that similar of normal flow conditions. In vivo, ligation injury–induced low flow increased vascular smooth muscle cell growth and vascular remodeling, although increasing Ptc-1/Notch expression. Perivascular delivery of Ptc-1 small interfering RNA by pluronic gel inhibited the pathological low flow–induced increases in Ptc-1/Notch expression and the subsequent increase in vascular remodeling. In addition, this pathological low flow–induced remodeling was returned to normal flow control levels after ptc-1 gene knockdown.
Conclusions—These results suggest that pathological low flow stimulates smooth muscle cell growth in vitro and vascular remodeling in vivo via Ptc-1 regulation of Notch signaling.
- Received April 17, 2013.
- Accepted May 28, 2013.
- © 2013 American Heart Association, Inc.