Abstract
ObjectivesTo determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling.Methods and ResultsCarotid 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.ConclusionThese results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA.
Highlights
Atherosclerosis and arterial occlusion as a result of flow-limiting stenosis is a leading cause of myocardial infarction and sudden death [34] [26]
These results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA
As similar changes are apparent during vasculogenesis and embryonic development [8] [4], we and others have postulated that the control of vascular smooth muscle cell (vSMC) growth and subsequent vascular remodeling in disease states and following injury may share similar signaling pathways
Summary
Atherosclerosis and arterial occlusion as a result of flow-limiting stenosis is a leading cause of myocardial infarction and sudden death [34] [26]. The arterial remodeling responsible for atherosclerosis is characterized by a vascular pathology where medial thickening, neointimal formation and subsequent narrowing of the lumen are the predominant features [26] [27] [1]. This remodeling can be outward and expansive or inward and constrictive and is characteristic of restenosis following balloon angioplasty and in transplant vasculopathy [5]. Changes in vascular smooth muscle cell (vSMC) growth and survival play an important role in medial thickening and neointimal formation during this arterial remodeling in response to injury, the mechanisms remain unclear [15] [11]. Several groups, including our own, have described a role for
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