Increased In-Stent Stenosis in ApoE Knockout Mice

Abstract

Objective-We aimed to develop and validate a model of angioplasty and stenting in mice that would allow investigation of the response to stent injury using genetically modified mouse strains. Methods and Results-Aortic segments from either C57BL/6 wild-type or atherosclerotic ApoE-KO mice underwent balloon angioplasty alone or balloon angioplasty and stenting with a 1.25ϫ2.5 mm stainless steel stent. Vessels were carotid-interposition grafted into genetically identical littermate recipients and harvested at 1, 7, 14, or 28 days. In wild-type mice, stenting generated an inflammatory vascular injury response between days 1 to 7, leading to the development of neointimal hyperplasia by day 14, which further increased in area by day 28 leading to the development of in-stent stenosis. Uninjured vessels and vessels injured by balloon angioplasty alone developed minimal neointimal hyperplasia. In stented ApoE-KO mice, neointimal area at 28 days was 30% greater compared with wild-type mice. Key Words: vascular biology Ⅲ genetically modified mice Ⅲ angioplasty Ⅲ stents Ⅲ restenosis P ercutaneous coronary intervention (PCI) is now the most commonly performed method of revascularization for coronary artery disease. The use of drug-eluting stents (DES), which target excessive smooth muscle cell proliferation and neointimal hyperplasia, has reduced clinical restenosis rates. However, current agents used for DES do not target inflammation or thrombosis, and may inhibit reendothelialization, 1 potentially increasing late thrombosis risk within the stented vessel. 2,3 Accordingly, there remains a pressing need to identify more rational, specific, and effective pharmacological targets in the vascular injury response to angioplasty and stenting. Conclusions-By See page 701Various experimental models have been used in the preclinical development of stenting, including rabbit, rat, and pig models. 4 Although these systems reproduce some aspects of the human vascular response to PCI, there are limitations in replicating the typical features of human atherosclerosis. In addition, constraints in genetic manipulation limit existing large-animal models to pharmacological and physical interventions, rather than dissection of relevant biological pathways by genomic approaches. In contrast, genetically-modified mice have provided important insights into the role of specific pathways in the pathophysiology of atherosclerosis and other vascular disease states. 5 Mouse models also provide refinements in laboratory animal use, are cost-effective, and have a favorable generation time for cross-breeding experiments. Although mouse models would provide powerful approaches to investigate molecular mechanisms relevant to angioplasty and stenting, technical challenges have restricted such studies in mice to surrogate models of vascular injury, such as wire-denudation of endothelium 6,7 or perivascular polyethylene cuff placement. 8 These models have significant limitations in their ability to address potentially important aspects of balloon angioplas...

Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1

“…We also found a corresponding time-dependent increase in phosphorylation of ROS1 at Y2274 ( Figure 5D), a phosphorylation site known to activate the kinase (21), which was in line with the time course of neointima development following vascular injury (5). Taken together, these findings suggest GSH reductive stress as a mediator of ROS1 phosphorylation and activation.…”

“…BAS was performed in 18-to 22-week-old mice as described previously (5). In order to be able to track endothelial cells by in situ hybridization for the Y chromosome, stent grafts were constructed using female donors and male recipient mice.…”

“…Aorta and stented vessels were excised, fixed in paraformaldehyde overnight, dehydrated in graded ethanol solution, and paraffin embedded or removed fresh and snap-frozen in either Trizol, OCT, or maintained fresh. Histomorphometric analysis of aortic atherosclerosis lesion area and stented vessel processing and analysis were performed as previously described (5). Immunohistochemistry was performed as described previously (45).…”

“…Considering that over 1 million patients undergo DES implantation each year within the United States (1), there remains a pressing need to identify more specific and effective pharmacological agents targeting neointimal hyperplasia without detrimental effects on reendothelialization. Accordingly, we developed and validated a mouse model of BAS that allows for interrogation of relevant molecular pathways by high-throughput genomic approaches not readily feasible using larger animal models (5).…”

2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease: Executive summary

“…The incidence of restenosis after CAS has been in the range of 3% to 5%. [215][216][217][218][219][220][221][222][223][224][225][226][227][228][229][230][231][232][233] The incidence of TIA has been reported as 1% to 2% in patients undergoing CAS. Intracranial hemorrhage and the hyperperfusion syndrome related to hypertension and anticoagulation have been reported as complications in <1% of CAS procedures.…”