Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling

• Published in: PloS one 2014-01, Vol.9 (1), p.e84122-e84122
• Main Authors: Redmond, Eileen M, Liu, Weimin, Hamm, Katie, Hatch, Ekaterina, Cahill, Paul A, Morrow, David
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Atherosclerosis; Bcl-x protein; Biology; Blood vessels; Carotid arteries; Carotid Arteries - metabolism; Carotid Arteries - pathology; Carotid Arteries - physiopathology; Carotid artery; Carotid Artery Injuries - pathology; Carotid Artery Injuries - physiopathology; Cell growth; Cell Proliferation; Comparative analysis; Gene expression; Gene Transfer Techniques; Genes; Growth factors; Injury prevention; Male; Medicine; Mice; Mice, Inbred C57BL; Morphometry; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Notch1 protein; Physiology; Proliferating cell nuclear antigen; Pulmonary arteries; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - metabolism; Signal Transduction; siRNA; Smooth muscle; Studies; Surgery; Thickening; Veins & arteries
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0084122

To determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling. Carotid artery ligation was performed to induce arterial remodeling. After 14 days, morphometric analysis confirmed increased vSMC growth and subsequent media thickening and neointimal formation. Laser capture microdissection, quantitative qRT-PCR and immunoblot analysis of medial tissue revealed a significant increase in Notch1 receptor and notch target gene, Hrt 1 and 2 expression in the injured vessels. Perivascular delivery of Notch 1 siRNA by pluronic gel inhibited the injury-induced increase in Notch 1 receptor and target gene expression when compared to scrambled siRNA controls while concomitantly reducing media thickening and neointimal formation to pre-injury, sham-operated levels. Selective Notch 1 knockdown also reversed the injury-induced inhibition of pro-apoptotic Bax expression while decreasing injury-induced anti-apoptotic Bcl-XL expression to sham-operated control levels. In parallel experiments, proliferative cyclin levels, as measured by PCNA expression, were reversed to sham-operated control levels following selective Notch 1 knockdown. These results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA.