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Emerging Topics in Smooth Muscle Cell Fate and Plasticity in...
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Emerging Topics in Smooth Muscle Cell Fate and Plasticity in Atherosclerosis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 30 June 2026 | Viewed by 2451

Special Issue Editors

Dr. Mandy Grootaert

E-Mail Website
Guest Editor
1. Endocrinology, Diabetes and Nutrition (EDIN), UCLouvain, Avenue Hippocrate 55, 1200 Brussels, Belgium
2. Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
Interests: smooth muscle cells; pericytes; vascular remodelling; atherosclerosis; cardiometabolic diseases; microvasculature; autophagy; cell death; cell senescence
Dr. Julián Albarrán-Juárez

E-Mail Website
Guest Editor
Atherosclerosis Research Unit, Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark
Interests: smooth muscle cells; atherosclerosis; mechanotransduction; cardiovascular disease; vascular biology

Special Issue Information

Dear Colleagues,

Recent lineage tracing studies in mice, in combination with single-cell technologies, revealed that vascular smooth muscle cells (VSMCs) are more abundant in atherosclerotic plaques (accounting for 40-70% of all plaque cells) and more plastic than initially thought. Indeed, VSMC can adopt many different phenotypes, including macrophage-like, foam cell-like, osteochondrogenic-like, and myofibroblast-like cells, a phenomenon called VSMC phenotypic modulation. Since some of these cell fates may be detrimental to plaque stability, identifying signals/mechanisms that maintain or regulate VSMC plasticity is essential to discover new therapeutic targets. Moreover, many technological advancements are emerging, from transcriptomics to metabolomics to high-resolution microscopic imaging, allowing further study of the impact of VSMC plasticity on plaque stability. The final goal is to exploit vascular heterogeneity to either develop strategies for risk stratification of patients or to facilitate the development of new anti-atherosclerotic therapies.

This collection welcomes submissions of research articles and review articles emphasising novel findings on VSMC plasticity and fate. Manuscripts on how other vascular cells (e.g., endothelial cells) affect VSMC plasticity and fate in atherosclerosis are also considered. We aim to bring together basic and translational research covering several aspects of VSMC heterogeneity and plasticity and its relevance for atherosclerosis. 

Dr. Mandy Grootaert
Dr. Julián Albarrán-Juárez
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • vascular smooth muscle cells
  • lineage tracing
  • fate mapping
  • VSMC plasticity
  • (single cell) (spatial) omics
  • vascular heterogeneity
  • atherosclerosis

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Published Papers (3 papers)

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Research

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23 pages, 3965 KB  
Article
C-Kit Is Essential for Vascular Smooth Muscle Cell Phenotypic Switch In Vitro and In Vivo After Injury
by Chiara Siracusa, Giovanni Canino, Mariangela Scalise, Fabiola Marino, Loredana Pagano, Gianluca Santamaria, Annalaura Torella, Salvatore De Rosa, Daniele Torella and Eleonora Cianflone
Cells 2025, 14(20), 1641; https://doi.org/10.3390/cells14201641 (registering DOI) - 21 Oct 2025
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Abstract
Pathological vascular remodeling—central to restenosis, atherosclerosis, and vasculo-proliferative diseases—depends on the phenotypic switching of vascular smooth muscle cells (VSMCs) from a quiescent, contractile state to a synthetic, proliferative program. Although the receptor tyrosine kinase c-Kit is implicated in proliferation, migration, and tissue repair, [...] Read more.
Pathological vascular remodeling—central to restenosis, atherosclerosis, and vasculo-proliferative diseases—depends on the phenotypic switching of vascular smooth muscle cells (VSMCs) from a quiescent, contractile state to a synthetic, proliferative program. Although the receptor tyrosine kinase c-Kit is implicated in proliferation, migration, and tissue repair, its role in VSMC plasticity has yet to be fully understood. Using c-Kit haploinsufficient mice subjected to right carotid artery ligation (CAL) and primary aortic VSMC cultures, we show that c-Kit is required for the contractile-to-synthetic transition. In vitro, c-Kit haploinsufficiency halved c-Kit expression, reduced 5-bromo-2′-deoxyuridine (BrdU) incorporation, and blunted platelet-derived growth factor BB (PDGF-BB)-induced repression of contractile genes. c-Kit–deficient VSMCs exhibited a senescence program with increased p16INK4a/p21 expression and upregulated senescence-associated secretory phenotype (SASP) mediators. RNA-Seq of carotid arteries 7 days post-ligation revealed that wild-type arteries activated cell-cycle pathways and suppressed contractile signatures, whereas c-Kit-deficient carotid arteries failed to fully engage proliferative programs and instead maintained contractile gene expression. At 28 days post CAL in vivo, c-Kit haploinsufficiency produced markedly reduced neointima, fewer Ki67+ VSMCs, more p16INK4a+ cells, and impaired re-endothelialization. Because progenitor-to-VSMC differentiation contributes to remodeling, we tested adult cardiac stem/progenitor cells (CSCs) as a model system of adult progenitor differentiation. Wild-type CSCs efficiently generated induced VSMCs (iVSMCs) with appropriate smooth-muscle gene upregulation; c-Kit–deficient rarely did so. Restoring c-Kit with a BAC transgene rescued both the smooth-muscle differentiation and proliferative competence of c-Kit-deficient iVSMCs. Collectively, our data identified c-Kit as a gatekeeper of reparative VSMC plasticity. Adequate c-Kit enables progenitor-to-VSMC commitment and the expansion of newly formed VSMCs while permitting injury-induced proliferation and matrix synthesis; reduced c-Kit locks cells in a hypercontractile, senescence-prone state and limits neointima formation. Modulating the c-Kit axis may therefore offer a strategy to fine-tune vascular repair while mitigating pathological remodeling. Full article
(This article belongs to the Special Issue Emerging Topics in Smooth Muscle Cell Fate and Plasticity in Atherosclerosis)
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23 pages, 3181 KB  
Article
Side-by-Side Comparison of Culture Media Uncovers Phenotypic and Functional Differences in Primary Mouse Aortic Mural Cells
by Iman Ghasemi, Rajinikanth Gogiraju, Sana’a Khraisat, Sven Pagel, Claudine Graf, Moritz Brandt, Thati Madhusudhan, Philip Wenzel, Guillermo Luxán, Philipp Lurz, Magdalena L. Bochenek and Katrin Schäfer
Cells 2025, 14(12), 927; https://doi.org/10.3390/cells14120927 - 19 Jun 2025
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Abstract
(1) Background: Vascular mural cells reside in the media and outer layers of the vessel wall. Their ability to proliferate and migrate or to change phenotype in response to external cues is a central feature of the vascular response to injury. Genetically engineered [...] Read more.
(1) Background: Vascular mural cells reside in the media and outer layers of the vessel wall. Their ability to proliferate and migrate or to change phenotype in response to external cues is a central feature of the vascular response to injury. Genetically engineered mice are used for loss- or gain-of-function analyses or lineage tracing in vivo, their primary cells for mechanistic studies in vitro. Whether and how cultivation conditions affect their phenotype and function is often overlooked. (2) Methods: Here, we systematically studied how the cultivation of primary mural cells isolated from the aorta of adult wild-type mice in either basal medium (DMEM) or special media formulated for the cultivation of fibroblasts or pericytes affects their phenotype and function. (3) Results: Medium composition did not alter cell viability, but the mRNA levels of differentiated smooth muscle cell markers were highest in vascular mural cells expanded in DMEM. Conversely, significantly higher numbers of proliferating and migrating cells were observed in cells expanded in Pericyte medium, and cytoskeletal rearrangements supported increased migratory capacities. Significantly reduced telomere lengths and metabolic reprogramming was observed in aortic mural cells cultured in Fibroblast medium. (4) Conclusions: Our findings underline the plasticity of primary aortic mural cells and highlight the importance of the culture media composition during their expansion, which could be exploited to interrogate their responsiveness to external stimuli or conditions observed in vivo or in patients. Full article
(This article belongs to the Special Issue Emerging Topics in Smooth Muscle Cell Fate and Plasticity in Atherosclerosis)
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Review

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24 pages, 3012 KB  
Review
Cellular and Molecular Mechanisms of VSMC Phenotypic Switching in Type 2 Diabetes
by Shreya Gupta, Gilbert Hernandez and Priya Raman
Cells 2025, 14(17), 1365; https://doi.org/10.3390/cells14171365 - 2 Sep 2025
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Abstract
Vascular smooth muscle cells (VSMCs) are a major cell type in the arterial wall responsible for regulating vascular homeostasis. Under physiological conditions, VSMCs reside in the medial layer of the arteries, express elevated levels of contractile proteins, regulate vascular tone, and provide mechanical [...] Read more.
Vascular smooth muscle cells (VSMCs) are a major cell type in the arterial wall responsible for regulating vascular homeostasis. Under physiological conditions, VSMCs reside in the medial layer of the arteries, express elevated levels of contractile proteins, regulate vascular tone, and provide mechanical strength and elasticity to the blood vessel. In response to obesity, hyperglycemia, and insulin resistance, critical pathogenic hallmarks of Type 2 diabetes (T2D), VSMCs undergo a phenotypic transformation, adopting new phenotypes with increased proliferative (synthetic), inflammatory (macrophage-like), or bone-like (osteogenic) properties. While crucial for normal repair and vascular adaptation, VSMC phenotypic plasticity is a key driver for the development and progression of macrovascular complications associated with T2D. Despite advances in lineage tracing and multi-omics profiling that have uncovered key molecular regulators of VSMC phenotypic switching in vasculopathy, our understanding of the cellular and molecular mechanisms underlying VSMC transformation into diseased phenotypes in T2D remains incomplete. This review will provide a holistic summary of research from the past 15 years, with a focus on the signaling pathways and transcriptional regulators that govern VSMC phenotypic transition in response to obesity, hyperglycemia, and insulin resistance. We examine the integrated molecular mechanisms that orchestrate VSMC fate reprogramming in T2D and highlight the dynamic interplay among diverse signaling and transcriptional networks. Emphasis is placed on how these interconnected pathways collectively influence VSMC behavior and contribute to the pathogenesis of T2D-associated atherosclerosis. Full article
(This article belongs to the Special Issue Emerging Topics in Smooth Muscle Cell Fate and Plasticity in Atherosclerosis)
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