Abstract 509: Inhibition of Patched-1 prevents Injury-induced Neointimal Hyperplasia
Intimal remodeling occurs due to alterations in vascular smooth muscle cell (VSMC) proliferation and apoptosis and is a key event in the pathogenesis of vascular disease. Atherosclerosis, vascular rejection, venous graft restenosis and coronary intervention are each characterized by increased VSMC growth and intimal thickening.
Objectives To determine the role of Ptc-1 in mediating pulsatile flow-induced changes in SMC growth and neointimal hyperplasia.
Methods and Results HCASMC were exposed to “normal“ or pathological “low” pulsatile flow conditions for 24 h by utilizing a perfused transcapillary flow system. In vivo, pathological low flow conditions following carotid artery ligation increased medial SMC growth while increasing Ptc-1/Notch expression. Inhibition of Ptc-1 expression by cyclopamine attenuated low flow-induced increases in VEGF/Notch expression while concomitantly decreasing HCASMC growth to normal flow levels. Perivascular delivery of Ptc-1 siRNA by pluronic gel inhibited the low flow-induced increases in Ptc-1/Notch expression and subsequent increase in medial SMC growth. In addition, low pulsatile flow-induced increases in neointimal hyperplasia and subsequent decreased lumen volume were returned to sham-operated control levels following ptc-1 gene knockdown.
Conclusion These results suggest that pathological low flow stimulates SMC growth and neointimal hyperplasia via Ptc-1 regulation of VEGF/Notch signaling.
- © 2013 by American Heart Association, Inc.