Suppression of neointima formation by targeting β-catenin/TCF pathway

Williams, Helen; Slater, S. D.; George, Sarah J.

doi:10.1042/bsr20160229

Cited by 9 publications

(13 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously shown that Wnt/β-catenin/TCF-activated VSMCs display higher migratory and proliferative rates and thereby contribute to intimal thickening 6, 7. Williams et al 4 . demonstrated that Ad-mediated delivery of the thymidine kinase (TK) gene driven by a Wnt/β-catenin/TCF-responsive promoter suppressed neointima formation in ligated carotid arteries of mice infused with ganciclovir.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that overexpression of dominant-negative N-cadherin (dn-N-cadherin), which consists of amino acids 6–27 (the cytoplasmic and transmembrane domains), in isolated VSMCs promoted apoptosis and reduced intimal thickening ex vivo 3 . We have also identified Wnt/β-catenin/T cell factor (TCF) signaling as a modulator of VSMC phenotype and contributor to intimal thickening 3, 4. In consideration of our previous findings, we have developed an adenovirus (Ad)-based vector, in which the pro-apoptotic dn-N-cadherin gene was driven by a Wnt/β-catenin/TCF-responsive promoter linked to a minimal cytomegalovirus (CMV) promoter.…”

Section: Introductionmentioning

confidence: 99%

“…We hypothesized that introduction of Ad-TOP-dn-N-cadherin (Ad-TOP-dn-N-cad) would reduce VSMC accumulation and impair neointima formation in both our ex vivo human saphenous vein (HSV) organ culture model and our in vivo mouse carotid artery ligation model. This suicide gene approach, targeted at specifically killing Wnt/β-catenin/TCF-activated VSMCs and preserving non-activated VSMCs, is similar to that successfully employed by Williams et al 4 . and Kwong et al 5 .…”

Section: Introductionmentioning

confidence: 99%

“… 3 We have also identified Wnt/β-catenin/T cell factor (TCF) signaling as a modulator of VSMC phenotype and contributor to intimal thickening. 3 , 4 In consideration of our previous findings, we have developed an adenovirus (Ad)-based vector, in which the pro-apoptotic dn-N-cadherin gene was driven by a Wnt/β-catenin/TCF-responsive promoter linked to a minimal cytomegalovirus (CMV) promoter. We hypothesized that introduction of Ad-TOP-dn-N-cadherin (Ad-TOP-dn-N-cad) would reduce VSMC accumulation and impair neointima formation in both our ex vivo human saphenous vein (HSV) organ culture model and our in vivo mouse carotid artery ligation model.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation

Hulin-Curtis

Williams

Wadey

et al. 2017

Molecular Therapy - Methods & Clinical Development

Self Cite

View full text Add to dashboard Cite

Approximately 50% of coronary artery bypass grafts using the autologous saphenous vein fail within 10 years due to intimal thickening. This study examined whether a gene therapy approach that selectively kills Wnt/β-catenin/T cell factor (TCF) activated vascular smooth muscle cells (VSMCs) using dominant-negative N-cadherin (dn-N-cadherin) reduced intimal thickening. Cultured human VSMCs infected with an adenovirus (Ad) encoding dn-N-cadherin via the TCF promoter (Ad-TOP-dn-N-cadherin) specifically expressed dn-N-cadherin in response to activation of the Wnt/β-catenin/TCF pathway. Infection with Ad-TOP-dn-N-cadherin significantly increased VSMC apoptosis (3 ± 0.2% versus 9 ± 0.7%; p < 0.05, n = 6) and significantly inhibited VSMC migration by 83 ± 15% (p < 0.05, n = 6), but did not affect VSMC proliferation (p > 0.05, n = 5). In an ex vivo human saphenous vein organ culture model, luminal delivery of Ad-TOP-dn-N-cadherin significantly increased VSMC apoptosis after 7 days of culture (4 ± 1.4% versus 9 ± 1.6%; p < 0.01, n = 6) and suppressed intimal thickening by 75 ± 7% (p < 0.05, n = 5), without a detrimental effect on endothelial cell coverage. In vivo, Ad-TOP-dn-N-cadherin significantly reduced intimal thickening at day 21 (n = 10) in comparison to the Ad-β-galactosidase (Ad-β-gal) control virus (n = 12, p < 0.05) in the mouse carotid artery ligation model. In summary, we have developed a novel approach to selectively reduce intimal thickening, which may be beneficial in reducing late vein graft failure.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation

Hulin-Curtis

Williams

Wadey

et al. 2017

Molecular Therapy - Methods & Clinical Development

Self Cite

View full text Add to dashboard Cite

show abstract

“…144 Two recent studies using the mouse carotid artery ligation model demonstrated that selective suicide of cells with active Wnt signalling retards intimal thickening. 145,146…”

Section: Cell-cell Contacts-cadherinsmentioning

confidence: 99%

Role of smooth muscle cells in coronary artery bypass grafting failure

Wadey

Lopes

Bendeck

et al. 2018

Cardiovascular Research

View full text Add to dashboard Cite

Atherosclerosis is the underlying pathology of many cardiovascular diseases. The formation and rupture of atherosclerotic plaques in the coronary arteries results in angina and myocardial infarction. Venous coronary artery bypass grafts are designed to reduce the consequences of atherosclerosis in the coronary arteries by diverting blood flow around the atherosclerotic plaques. However, vein grafts suffer a high failure rate due to intimal thickening that occurs as a result of vascular cell injury and activation and can act as 'a soil' for subsequent atherosclerotic plaque formation. A clinically-proven method for the reduction of vein graft intimal thickening and subsequent major adverse clinical events is currently not available. Consequently, a greater understanding of the underlying mechanisms of intimal thickening may be beneficial for the design of future therapies for vein graft failure. Vein grafting induces inflammation and endothelial cell damage and dysfunction, that promotes vascular smooth muscle cell (VSMC) migration, and proliferation. Injury to the wall of the vein as a result of grafting leads to the production of chemoattractants, remodelling of the extracellular matrix and cell-cell contacts; which all contribute to the induction of VSMC migration and proliferation. This review focuses on the role of altered behaviour of VSMCs in the vein graft and some of the factors which critically lead to intimal thickening that pre-disposes the vein graft to further atherosclerosis and re-occurrence of symptoms in the patient.

show abstract

Stent‐mediated gene and drug delivery for cardiovascular disease and cancer: A brief insight

Krishnagopal

Reddy

Sen

2017

The Journal of Gene Medicine

View full text Add to dashboard Cite

This review concisely recapitulates the different existing modes of stent-mediated gene/drug delivery, their considerable advancement in clinical trials and a rationale for other merging new technologies such as nanotechnology and microRNA-based therapeutics, in addition to addressing the limitations in each of these perpetual stent platforms. Over the past decade, stent-mediated gene/drug delivery has materialized as a hopeful alternative for cardiovascular disease and cancer in contrast to routine conventional treatment modalities. Regardless of the phenomenal recent developments achieved by coronary interventions and cancer therapies that employ gene and drug-eluting stents, practical hurdles still remain a challenge. The present review highlights the limitations that each of the existing stent-based gene/drug delivery system encompasses and therefore provides a vision for the future with respect to discovering an ideal stent therapeutic platform that would circumvent all the practical hurdles witnessed with the existing technology. Further study of the improvisation of next-generation drug-eluting stents has helped to overcome the issue of restenosis to some extent. However, current stent formulations fall short of the anticipated clinically meaningful outcomes and there is an explicit need for more randomized trials aiming to further evaluate stent platforms in favour of enhanced safety and clinical value. Gene-eluting stents may hold promise in contributing new ideas for stent-based prevention of in-stent restenosis through genetic interventions by capitalizing on a wide variety of molecular targets. Therefore, the central consideration directs us toward finding an ideal stent therapeutic platform that would tackle all of the gaps in the existing technology.

show abstract

Suppression of neointima formation by targeting β-catenin/TCF pathway

Cited by 9 publications

References 17 publications

Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation

Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation

Role of smooth muscle cells in coronary artery bypass grafting failure

Stent‐mediated gene and drug delivery for cardiovascular disease and cancer: A brief insight

Contact Info

Product

Resources

About