Vascular smooth muscle cells in intimal hyperplasia, an update

Déglise, Sebastien; Bechelli, Clémence; Allagnat, Florent

doi:10.3389/fphys.2022.1081881

Cited by 35 publications

(29 citation statements)

References 290 publications

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“…TSP‐2, which is primarily produced by SMC and fibroblasts, has been described to be an important modulator of cell‐matrix interactions and regulator of SMC and EC proliferation 27,36 . TSP‐2 role in increasing SMC proliferation, a key step in the formation of IH, has been clearly described 37,38 . Our study suggested that the downregulation of TSP‐2 inhibits this dysregulated proliferation of cells, as demonstrated by the decrease of Ki‐67 in CCA treated with CLICK‐gelatin + TSP‐2 siRNA.…”

Section: Discussionsupporting

confidence: 55%

“…27,36 TSP-2 role in increasing SMC proliferation, a key step in the formation of IH, has been clearly described. 37,38 Our study suggested that the downregulation of TSP-2 inhibits this dysregulated proliferation of cells, as demonstrated by the decrease of Ki-67 in CCA treated with CLICK-gelatin + TSP-2 siRNA. Further supporting inhibition of cell proliferation as an important mechanism of TSP-2 downregulation in attenuating IH formation.…”

Section: Discussionmentioning

confidence: 63%

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Perivascular CLICK‐gelatin delivery of thrombospondin‐2 small interfering RNA decreases development of intimal hyperplasia after arterial injury

Mota,

Zhu,

et al. 2023

The FASEB Journal

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Bypass graft failure occurs in 20%–50% of coronary and lower extremity bypasses within the first‐year due to intimal hyperplasia (IH). TSP‐2 is a key regulatory protein that has been implicated in the development of IH following vessel injury. In this study, we developed a biodegradable CLICK‐chemistry gelatin‐based hydrogel to achieve sustained perivascular delivery of TSP‐2 siRNA to rat carotid arteries following endothelial denudation injury. At 21 days, perivascular application of TSP‐2 siRNA embedded hydrogels significantly downregulated TSP‐2 gene expression, cellular proliferation, as well as other associated mediators of IH including MMP‐9 and VEGF‐R2, ultimately resulting in a significant decrease in IH. Our data illustrates the ability of perivascular CLICK‐gelatin delivery of TSP‐2 siRNA to mitigate IH following arterial injury.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 63%

Perivascular CLICK‐gelatin delivery of thrombospondin‐2 small interfering RNA decreases development of intimal hyperplasia after arterial injury

Mota,

Zhu,

et al. 2023

The FASEB Journal

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“…Importantly, migration of fibroblasts to the intima plays a well-documented role in the development of intimal hyperplasia and atherosclerosis. 59 Within the intima of distended veins, myeloid cells are also enriched, further underscoring the recruitment and infiltration of immune cells initiated by the effects of distension on the endothelium. Lastly, SMCs display increased enrichment in the adventitia of distended veins, supporting our hypothesis that while the overall proportion of SMCs decreases following distension, SMCs present in the distended veins may undergo VSMC-reprogramming toward a synthetic phenotype facilitating their migration to the adventitia.…”

Section: Resultsmentioning

confidence: 98%

Integrated single-nuclei and spatial transcriptomic analysis reveals propagation of early acute vein harvest and distension injury signaling pathways following arterial implantation

Michaud,

Mota,

Bakhtiari

et al. 2023

Preprint

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BackgroundVein graft failure (VGF) following cardiovascular bypass surgery results in significant patient morbidity and cost to the healthcare system. Vein graft injury can occur during autogenous vein harvest and preparation, as well as after implantation into the arterial system, leading to the development of intimal hyperplasia, vein graft stenosis, and, ultimately, bypass graft failure. While previous studies have identified maladaptive pathways that occur shortly after implantation, the specific signaling pathways that occur during vein graft preparation are not well defined and may result in a cumulative impact on VGF. We, therefore, aimed to elucidate the response of the vein conduit wall during harvest and following implantation, probing the key maladaptive pathways driving graft failure with the overarching goal of identifying therapeutic targets for biologic intervention to minimize these natural responses to surgical vein graft injury.MethodsEmploying a novel approach to investigating vascular pathologies, we harnessed both single-nuclei RNA-sequencing (snRNA-seq) and spatial transcriptomics (ST) analyses to profile the genomic effects of vein grafts after harvest and distension, then compared these findings to vein grafts obtained 24-hour after carotid-cartoid vein bypass implantation in a canine model (n=4).ResultsSpatial transcriptomic analysis of canine cephalic vein after initial conduit harvest and distention revealed significant enrichment of pathways (P< 0.05) involved in the activation of endothelial cells (ECs), fibroblasts (FBs), and vascular smooth muscle cells (VSMCs), namely pathways responsible for cellular proliferation and migration and platelet activation across the intimal and medial layers, cytokine signaling within the adventitial layer, and extracellular matrix (ECM) remodeling throughout the vein wall. Subsequent snRNA-seq analysis supported these findings and further unveiled distinct EC and FB subpopulations with significant upregulation (P< 0.00001) of markers related to endothelial injury response and cellular activation of ECs, FBs, and VSMCs. Similarly, in vein grafts obtained 24 hours after arterial bypass, there was an increase in myeloid cell, protomyofibroblast, injury-response EC, and mesenchymal-transitioning EC subpopulations with a concomitant decrease in homeostatic ECs and fibroblasts. Among these markers were genes previously implicated in vein graft injury, includingVCAN(versican),FBN1(fibrillin-1), andVEGFC(vascular endothelial growth factor C), in addition to novel genes of interest such asGLIS3(GLIS family zinc finger 3) andEPHA3(ephrin-A3). These genes were further noted to be driving the expression of genes implicated in vascular remodeling and graft failure, such asIL-6,TGFBR1,SMAD4, andADAMTS9.By integrating the ST and snRNA-seq datasets, we highlighted the spatial architecture of the vein graft following distension, wherein activated and mesenchymal-transitioning ECs, myeloid cells, and FBs were notably enriched in the intima and media of distended veins. Lastly, intercellular communication network analysis unveiled the critical roles of activated ECs, mesenchymal transitioning ECs, protomyofibroblasts, and VSMCs in upregulating signaling pathways associated with cellular proliferation (MDK, PDGF, VEGF), transdifferentiation (Notch), migration (ephrin, semaphorin), ECM remodeling (collagen, laminin, fibronectin), and inflammation (thrombospondin), following distension.ConclusionsVein conduit harvest and distension elicit a prompt genomic response facilitated by distinct cellular subpopulations heterogeneously distributed throughout the vein wall. This response was found to be further exacerbated following vein graft implantation, resulting in a cascade of maladaptive gene regulatory networks. Together, these results suggest that distension initiates the upregulation of pathological pathways that may ultimately contribute to bypass graft failure and presents potential early targets warranting investigation for targeted therapies. This work highlights the first applications of single-nuclei and spatial transcriptomic analyses to investigate venous pathologies, underscoring the utility of these methodologies and providing a foundation for future investigations.

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“…This is due to their composition, which includes polymer cores and lipid/lipid‐PEG shells (Hadinoto et al, 2013) (Figure 3d). Intimal hyperplasia and a high level of lipid and platelet adhesion following localized injury caused by the stent can be counteracted by a prohealing, noncytotoxic remodeling approach for the repression of SMC lipid uptake and hyperproliferation, which could be effective in preventing further oxidative stress, SMC proliferation, and platelet adhesion within stented arteries (Chan et al, 2016; Déglise et al, 2022). Chan et al reported that the lipid hybrid NP‐based therapy causes effective vascular targeting and controlled drug release.…”

Section: Stents Coated With Nanoparticle‐based Therapeuticsmentioning

confidence: 99%

Nanotechnology in development of next generation of stent and related medical devices: Current and future aspects

Islam,

Schaly,

Abosalha

et al. 2024

WIREs Nanomed Nanobiotechnol

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Coronary stents have saved millions of lives in the last three decades by treating atherosclerosis especially, by preventing plaque protrusion and subsequent aneurysms. They attenuate the vascular SMC proliferation and promote reconstruction of the endothelial bed to ensure superior revascularization. With the evolution of modern stent types, nanotechnology has become an integral part of stent technology. Nanocoating and nanosurface fabrication on metallic and polymeric stents have improved their drug loading capacity as well as other mechanical, physico‐chemical, and biological properties. Nanofeatures can mimic the natural nanofeatures of vascular tissue and control drug‐delivery. This review will highlight the role of nanotechnology in addressing the challenges of coronary stents and the recent advancements in the field of related medical devices. Different generations of stents carrying nanoparticle‐based formulations like liposomes, lipid‐polymer hybrid NPs, polymeric micelles, and dendrimers are discussed highlighting their roles in local drug delivery and anti‐restenotic properties. Drug nanoparticles like Paclitaxel embedded in metal stents are discussed as a feature of first‐generation drug‐eluting stents. Customized precision stents ensure safe delivery of nanoparticle‐mediated genes or concerted transfer of gene, drug, and/or bioactive molecules like antibodies, gene mimics via nanofabricated stents. Nanotechnology can aid such therapies for drug delivery successfully due to its easy scale‐up possibilities. However, limitations of this technology such as their potential cytotoxic effects associated with nanoparticle delivery that can trigger hypersensitivity reactions have also been discussed in this review.This article is categorized under: Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies

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Vascular smooth muscle cells in intimal hyperplasia, an update

Cited by 35 publications

References 290 publications

Perivascular CLICK‐gelatin delivery of thrombospondin‐2 small interfering RNA decreases development of intimal hyperplasia after arterial injury

Perivascular CLICK‐gelatin delivery of thrombospondin‐2 small interfering RNA decreases development of intimal hyperplasia after arterial injury

Integrated single-nuclei and spatial transcriptomic analysis reveals propagation of early acute vein harvest and distension injury signaling pathways following arterial implantation

Nanotechnology in development of next generation of stent and related medical devices: Current and future aspects

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