Role of Vascular Smooth Muscle Cells in Cardiovascular Disease

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

Deadline for manuscript submissions: closed (31 December 2024) | Viewed by 35738

Special Issue Editors


E-Mail Website
Guest Editor
Department of Medicine, Emory University, Atlanta, GA, USA
Interests: vascular smooth muscle cell; cardiovascular disease

E-Mail Website
Guest Editor Assistant
Division of Cardiology, Emory University, Atlanta, GA, USA
Interests: vascular smooth muscle cell (VSMC); cardiovascular disease

Special Issue Information

Dear Colleagues,

Cardiovascular diseases are the leading cause of death worldwide. Vascular smooth muscle cells (VSMCs), a main component of the vessel wall, are essential to vascular function. Physiologically, VSMCs control vascular tone and diameter, respond to biomechanical forces initiated by hemodynamic changes and participate in determining vascular wall stiffness. VSMCs are not terminally differentiated and undergo phenotypic switching under pathological conditions, which is a component of many cardiovascular diseases, including atherosclerosis, stroke, myocardial infarction, and peripheral artery disease (PAD). Plasticity of VSMCs is necessary for vascular development and response to injury, but simultaneously implies susceptibility to vascular disease. With various stimuli, including endothelial injury, growth factors and altered metabolic function, VSMCs can dedifferentiate into a more proliferative, synthetic phenotype, and even transdifferentiate into macrophage-like, adipocyte-like or osteoblast-like cells. It is widely accepted that modulation, migration, proliferation and phenotypic switching of VSMCs play a role in a wide array of vascular diseases. Current treatments for vascular disease target lipid accumulation but fail to comprehensively account for the extensive role VSMCs play in disease formation and progression. In this Special Issue, we aim to highlight recent developments and advances in the understanding of how VSMCs function in cardiovascular disease progression mechanistically, molecularly, and cellularly. We welcome original and review articles that address VSMC pathophysiology in various contexts.

Dr. Alejandra San Martin
Guest Editor
Claire Holden 
Guest Editor Assistant

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

  • cardiovascular disease
  • vascular smooth muscle cell (VSMC)
  • phenotypic modulation
  • VSMC migration
  • atherosclerosis
  • VSMC plasticity
  • vascular injury
  • foam cells
  • stroke
  • myocardial infarction
  • peripheral artery disease (PAD)
  • restenosis
  • inflammation
  • metabolism

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (12 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

15 pages, 2343 KiB  
Article
YTH N6-methyladenosine RNA Binding Protein 1 Inhibits Smooth Muscle Cell Phenotypic Modulation and Neointimal Hyperplasia
by Kai Tian, Dunpeng Cai, Shuang Yang, Wen Zhao, Xiaohan Mei and Shi-You Chen
Cells 2025, 14(3), 160; https://doi.org/10.3390/cells14030160 - 22 Jan 2025
Viewed by 1030
Abstract
Smooth muscle cell (SMC) phenotypic transition contributes to several major vascular diseases such as intimal hyperplasia and restenosis, atherosclerosis, and aneurysm. However, the molecular mechanisms underlying this process are not fully understood. The objectives of this study are to determine the role of [...] Read more.
Smooth muscle cell (SMC) phenotypic transition contributes to several major vascular diseases such as intimal hyperplasia and restenosis, atherosclerosis, and aneurysm. However, the molecular mechanisms underlying this process are not fully understood. The objectives of this study are to determine the role of mRNA N6-methyladenosine (m6A) modification in SMC phenotypic modulation and injury-induced neointima formation. By using an m6A quantification kit, we found that m6A levels are altered during the early stage of SMC phenotypic modulation. RNA sequencing revealed that m6A modifications in the mRNAs of 708 genes are elevated while modifications in the mRNAs of 300 genes are decreased. These modifications occur in genes widely distributed in most chromosomes and involved in many cellular processes and signaling/gene regulations. Meanwhile, the regulators for m6A modifications are altered by PDGF-BB, a known factor inducing SMC phenotypic modulation. Although m6A writers and erasers are not altered during SMC phenotypic modulation, m6A reader YTHDF1 is dramatically reduced as early as 12 h following PDGF-BB treatment, a time much earlier than the downregulation of SMC contractile proteins. Importantly, the overexpression of YTHDF1 reverses the expression of SMC contractile proteins, suggesting a restoration of contractile SMC phenotype. By using a rat carotid artery balloon-injury model, we found that injury significantly decreases YTHDF1 levels in the medial SMCs while inducing neointima formation. Of significance, restoring YTHDF1 expression through lentiviral transduction blocks injury-induced neointima formation. Moreover, YTHDF1 delivery restores the expression of SMC contractile proteins that is diminished in arterial media layers due to the injury. These data demonstrate that YTHDF1 plays a protective role in maintaining the contractile SMC phenotype and vascular homeostasis during injury-induced pathological vascular remodeling. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Figure 1

19 pages, 4549 KiB  
Article
The Influence of Cell Isolation and Culturing on Natriuretic Peptide Receptors in Aortic Vascular Smooth Muscle Cells
by Christine Rager, Tobias Klöpper, Sabine Tasch, Michael Raymond Whittaker, Betty Exintaris, Andrea Mietens and Ralf Middendorff
Cells 2025, 14(1), 51; https://doi.org/10.3390/cells14010051 - 4 Jan 2025
Viewed by 1096
Abstract
Vascular smooth muscle cell (SMC) relaxation by guanylyl cyclases (GCs) and cGMP is mediated by NO and its receptor soluble GC (sGC) or natriuretic peptides (NPs) ANP/BNP and CNP with the receptors GC-A and GC-B, respectively. It is commonly accepted that cultured SMCs [...] Read more.
Vascular smooth muscle cell (SMC) relaxation by guanylyl cyclases (GCs) and cGMP is mediated by NO and its receptor soluble GC (sGC) or natriuretic peptides (NPs) ANP/BNP and CNP with the receptors GC-A and GC-B, respectively. It is commonly accepted that cultured SMCs differ from those in intact vessels. Nevertheless, cell culture often remains the first step for signaling investigations and drug testing. Previously, we showed that even popular reference genes changed dramatically after SMC isolation from aorta. Regarding NP receptors, a substantial amount of data relies on cell culture. We hypothesize that the NP/cGMP system in intact aortic tunica media differs from isolated and cultured aortic SMCs. Therefore, we studied isolation and culturing effects on the expression of NP receptors GC-A, GC-B, and NP clearance receptor (NPRC) compared to sGC. We investigated intact tunica media and primary SMCs from the longitudinal halves of the same rat aorta. GC activity was monitored by cyclic guanosine monophosphate (cGMP). In addition, we hypothesize that there are sex-dependent differences in the NP/cGMP cascade in both intact tissue and cultured cells. We, therefore, analyzed a male and female cohort. Expression was quantified by RT-qPCR comparing aortic media and SMCs with our recently validated reference gene (RG) small nuclear ribonucleoprotein 2 (U2). Only GC-A was stably expressed. In intact media, GC-A exceeded GC-B and NPRC. However, GC-B, NPRC, and sGC were dramatically upregulated in cultured SMCs of the same aortae different from the stable GC-A. The expression was mirrored by NP-induced GC activity. In cultured cells, changes in GC activity were delayed compared to receptor expression. Minor differences between both sexes could also be revealed. Thus, isolation and culture fundamentally alter the cGMP system in vascular SMCs with potential impact on drug testing and scRNAseq. Especially, the dramatic increase in the clearance receptor NPRC in culture might distort all physiological ANP, BNP, and CNP effects. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Figure 1

13 pages, 1311 KiB  
Article
Exploring Bone Morphogenetic Protein-2 and -4 mRNA Expression and Their Receptor Assessment in a Dynamic In Vitro Model of Vascular Calcification
by Manuela Cabiati, Federico Vozzi, Elisa Ceccherini, Letizia Guiducci, Elisa Persiani, Ilaria Gisone, Agnese Sgalippa, Antonella Cecchettini and Silvia Del Ry
Cells 2024, 13(24), 2091; https://doi.org/10.3390/cells13242091 - 18 Dec 2024
Cited by 2 | Viewed by 877
Abstract
Background: Vascular calcification (VC) is a dynamic, tightly regulated process driven by cellular activity and resembling the mechanisms of bone formation, with specific molecules playing pivotal roles in its progression. We aimed to investigate the involvement of the bone morphogenic proteins (BMP-2 [...] Read more.
Background: Vascular calcification (VC) is a dynamic, tightly regulated process driven by cellular activity and resembling the mechanisms of bone formation, with specific molecules playing pivotal roles in its progression. We aimed to investigate the involvement of the bone morphogenic proteins (BMP-2, BMP-4, BMPR-1a/1b, and BMPR-2) system in this process. Our study used an advanced in vitro model that simulates the biological environment of the vascular wall, assessing the ability of a phosphate mixture to induce the osteoblastic switch in human coronary artery smooth muscle cells (HCASMCs). Methods: HCASMCs were grown in mono- and co-culture with human coronary artery endothelial cells (HCAECs) in a double-flow bioreactor (LiveBox2 and IVTech), allowing static and dynamic conditions through a peristaltic pump. The VC was stimulated by incubation in a calcifying medium for 7 days. A BMP system Real-Time PCR was performed at the end of each experiment. Results: In monocultures, BMP-2 expression increased in calcified HCASMCs in static (p = 0.01) and dynamic conditions. BMP-4 and the biological receptors were expressed in all the experimental settings, increasing mainly in dynamic flow conditions. In co-cultures, we observed a marked increase in BMP-2 and BMP-4, BMPR-1a (p = 0.04 and p = 0.01, respectively), and BMPR-2 (p = 0.001) in the calcifying setting mostly in dynamic conditions. Conclusions: The increase in BMP-2/4 in co-culture suggests that these genes might promote the switch towards an osteogenic-like phenotype, data also supported by the rise of both BMPR-1a and BMPR-2. Thus, our findings provide insights into the mechanisms by which dynamic co-culture modulates the BMP system activation in an environment mimicking in vivo VC’s cellular and mechanical characteristics. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Figure 1

15 pages, 16991 KiB  
Article
ADAR1 Is Essential for Smooth Muscle Homeostasis and Vascular Integrity
by Dunpeng Cai and Shi-You Chen
Cells 2024, 13(15), 1257; https://doi.org/10.3390/cells13151257 - 26 Jul 2024
Cited by 1 | Viewed by 1579
Abstract
Vascular smooth muscle cells (VSMCs) play a critical role in maintaining vascular integrity. VSMC dysfunction leads to numerous vascular diseases. Adenosine deaminases acting on RNA 1 (ADAR1), an RNA editing enzyme, has shown both RNA editing and non-editing functions. Global deletion of ADAR1 [...] Read more.
Vascular smooth muscle cells (VSMCs) play a critical role in maintaining vascular integrity. VSMC dysfunction leads to numerous vascular diseases. Adenosine deaminases acting on RNA 1 (ADAR1), an RNA editing enzyme, has shown both RNA editing and non-editing functions. Global deletion of ADAR1 causes embryonic lethality, but the phenotype of homozygous ADAR1 deletion specifically in SMCs (ADAR1sm-/-) remains to be determined. By crossing ADAR1fl/fl mice with Myh11-CreERT2 mice followed by Tamoxifen induction, we found that ADAR1sm-/- leads to lethality in adult mice 14 days after the induction. Gross examination revealed extensive hemorrhage and detrimental vascular damage in different organs. Histological analyses revealed destruction of artery structural integrity with detachment of elastin laminae from VSMCs in ADAR1sm-/- aortas. Furthermore, ADAR1sm-/- resulted in severe VSMC apoptosis and mitochondrial dysfunction. RNA sequencing analyses of ADAR1sm-/- aorta segments demonstrated profound transcriptional alteration of genes impacting vascular health including a decrease in fibrillin-1 expression. More importantly, ADAR1sm-/- disrupts the elastin and fibrillin-1 interaction, a molecular event essential for artery structure. Our results indicate that ADAR1 plays a critical role in maintaining SMC survival and vascular stability and resilience. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Graphical abstract

14 pages, 2565 KiB  
Article
The Role of Fatty Acid Synthase in the Vascular Smooth Muscle Cell to Foam Cell Transition
by Bethany J. Bogan, Holly C. Williams, Claire M. Holden, Vraj Patel, Giji Joseph, Christopher Fierro, Hugo Sepulveda, W. Robert Taylor, Amir Rezvan and Alejandra San Martin
Cells 2024, 13(8), 658; https://doi.org/10.3390/cells13080658 - 9 Apr 2024
Cited by 4 | Viewed by 2523
Abstract
Vascular smooth muscle cells (VSMCs), in their contractile and differentiated state, are fundamental for maintaining vascular function. Upon exposure to cholesterol (CHO), VSMCs undergo dedifferentiation, adopting characteristics of foam cells—lipid-laden, macrophage-like cells pivotal in atherosclerotic plaque formation. CHO uptake by VSMCs leads to [...] Read more.
Vascular smooth muscle cells (VSMCs), in their contractile and differentiated state, are fundamental for maintaining vascular function. Upon exposure to cholesterol (CHO), VSMCs undergo dedifferentiation, adopting characteristics of foam cells—lipid-laden, macrophage-like cells pivotal in atherosclerotic plaque formation. CHO uptake by VSMCs leads to two primary pathways: ABCA1-mediated efflux or storage in lipid droplets as cholesterol esters (CEs). CE formation, involving the condensation of free CHO and fatty acids, is catalyzed by sterol O-acyltransferase 1 (SOAT1). The necessary fatty acids are synthesized by the lipogenic enzyme fatty acid synthase (FASN), which we found to be upregulated in atherosclerotic human coronary arteries. This observation led us to hypothesize that FASN-mediated fatty acid biosynthesis is crucial in the transformation of VSMCs into foam cells. Our study reveals that CHO treatment upregulates FASN in human aortic SMCs, concurrent with increased expression of CD68 and upregulation of KLF4, markers associated with the foam cell transition. Crucially, downregulation of FASN inhibits the CHO-induced upregulation of CD68 and KLF4 in VSMCs. Additionally, FASN-deficient VSMCs exhibit hindered lipid accumulation and an impaired transition to the foam cell phenotype following CHO exposure, while the addition of the fatty acid palmitate, the main FASN product, exacerbates this transition. FASN-deficient cells also show decreased SOAT1 expression and elevated ABCA1. Notably, similar effects are observed in KLF4-deficient cells. Our findings demonstrate that FASN plays an essential role in the CHO-induced upregulation of KLF4 and the VSMC to foam cell transition and suggest that targeting FASN could be a novel therapeutic strategy to regulate VSMC phenotypic modulation. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Graphical abstract

20 pages, 8275 KiB  
Article
AKT Mediates Adiponectin-Dependent Regulation of VSMC Phenotype
by Abigail E. Cullen, Ann M. Centner, Riley Deitado, Ahmed Ismaeel, Panagiotis Koutakis, Judy Muller-Delp and Gloria Salazar
Cells 2023, 12(20), 2493; https://doi.org/10.3390/cells12202493 - 20 Oct 2023
Cited by 7 | Viewed by 2344
Abstract
Adiponectin (adipoq), the most abundant hormone in circulation, has many beneficial effects on the cardiovascular system, in part by preserving the contractile phenotype of vascular smooth muscle cells (VSMCs). However, the lack of adiponectin or its receptor and treatment with recombinant adiponectin have [...] Read more.
Adiponectin (adipoq), the most abundant hormone in circulation, has many beneficial effects on the cardiovascular system, in part by preserving the contractile phenotype of vascular smooth muscle cells (VSMCs). However, the lack of adiponectin or its receptor and treatment with recombinant adiponectin have shown contradictory effects on plaque in mice. RNA sequence of Adipoq+/+ and adipoq−/− VSMCs from male aortas identified a critical role for adiponectin in AKT signaling, the extracellular matrix (ECM), and TGF-β signaling. Upregulation of AKT activity mediated proliferation and migration of adipoq−/− cells. Activation of AMPK with metformin or AdipoRon reduced AKT-dependent proliferation and migration of adipoq−/− cells but did not improve the expression of contractile genes. Adiponectin deficiency impaired oxidative phosphorylation (OXPHOS), increased expression of glycolytic enzymes, and elevated mitochondrial reactive oxygen species (ROS) (superoxide, and hydrogen peroxide). Anti-atherogenic mechanisms targeted the ECM in adipoq−/− cells, downregulating MMP2 and 9 and upregulating decorin (DCN) and elastin (ELN). In vivo, the main sex differences in protein expression in aortas involved a more robust upregulation of MMP3 in females than males. Females also showed a reduction in DCN, which was not affected in males. Our study uncovered the AKT/MAPK/TGF-β network as a central regulator of VSMC phenotype. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Graphical abstract

21 pages, 4862 KiB  
Article
Characterisation of Lipoma-Preferred Partner as a Novel Mechanotransducer in Vascular Smooth Muscle Cells
by Alexandra Sporkova, Taslima Nahar, Mingsi Cao, Subhajit Ghosh, Carla Sens-Albert, Prisca Amayi Patricia Friede, Anika Nagel, Jaafar Al-Hasani and Markus Hecker
Cells 2023, 12(18), 2315; https://doi.org/10.3390/cells12182315 - 19 Sep 2023
Viewed by 10432
Abstract
In arteries and arterioles, a chronic increase in blood pressure raises wall tension. This continuous biomechanical strain causes a change in gene expression in vascular smooth muscle cells (VSMCs) that may lead to pathological changes. Here we have characterised the functional properties of [...] Read more.
In arteries and arterioles, a chronic increase in blood pressure raises wall tension. This continuous biomechanical strain causes a change in gene expression in vascular smooth muscle cells (VSMCs) that may lead to pathological changes. Here we have characterised the functional properties of lipoma-preferred partner (LPP), a Lin11–Isl1–Mec3 (LIM)-domain protein, which is most closely related to the mechanotransducer zyxin but selectively expressed by smooth muscle cells, including VSMCs in adult mice. VSMCs isolated from the aorta of LPP knockout (LPP-KO) mice displayed a higher rate of proliferation than their wildtype (WT) counterparts, and when cultured as three-dimensional spheroids, they revealed a higher expression of the proliferation marker Ki 67 and showed greater invasion into a collagen gel. Accordingly, the gelatinase activity was increased in LPP-KO but not WT spheroids. The LPP-KO spheroids adhering to the collagen gel responded with decreased contraction to potassium chloride. The relaxation response to caffeine and norepinephrine was also smaller in the LPP-KO spheroids than in their WT counterparts. The overexpression of zyxin in LPP-KO VSMCs resulted in a reversal to a more quiescent differentiated phenotype. In native VSMCs, i.e., in isolated perfused segments of the mesenteric artery (MA), the contractile responses of LPP-KO segments to potassium chloride, phenylephrine or endothelin-1 did not vary from those in isolated perfused WT segments. In contrast, the myogenic response of LPP-KO MA segments was significantly attenuated while zyxin-deficient MA segments displayed a normal myogenic response. We propose that LPP, which we found to be expressed solely in the medial layer of different arteries from adult mice, may play an important role in controlling the quiescent contractile phenotype of VSMCs. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Figure 1

17 pages, 7093 KiB  
Article
Reference Gene U2 Enables Direct Comparison between Relative Gene Expression Levels of Vascular Smooth Muscle Cells in Tissue and Culture Using Real-Time Quantitative PCR
by Christine Rager, Tobias Klöpper, Uwe Pfeil, Sabine Tasch, Michael Raymond Whittaker, Betty Exintaris, Andrea Mietens and Ralf Middendorff
Cells 2023, 12(17), 2135; https://doi.org/10.3390/cells12172135 - 23 Aug 2023
Cited by 1 | Viewed by 1942
Abstract
In nearly every lab, real-time quantitative polymerase chain reaction (qPCR) is used to quantify gene expression. However, a comparison of different samples requires the careful selection of suitable reference genes (RGs), sometimes referred to as housekeeping genes. In the case of vascular smooth [...] Read more.
In nearly every lab, real-time quantitative polymerase chain reaction (qPCR) is used to quantify gene expression. However, a comparison of different samples requires the careful selection of suitable reference genes (RGs), sometimes referred to as housekeeping genes. In the case of vascular smooth muscle cells (vSMCs), it is important to know under which conditions gene expression in isolated and cultured vSMCs can be compared with vSMCs in a healthy blood vessel. We isolated the vSMC-containing layer of the rat aorta (tunica media) and used one (longitudinal) half for direct RNA extraction, while the other half served to isolate and culture vSMCs prior to RNA extraction. First, the expression of the routinely used RGs beta-actin (Actb) and Glyceraldehyde-3-phosphate dehydrogenase (Gapdh) is investigated in intact media and corresponding cultured vSMCs. Significant differences in their Ct values show that these RGs could not be used for such direct comparisons; therefore, we select 15 different RGs. Only the gene expression of the small ribonuclear protein (snRNP) U2 shows no significant differences between the absolute Ct values of cultured vSMCs and the intact media; moreover, no differences were found between male and female rats in our experimental setup. In conclusion, U2 was shown to be an appropriate (sex-independent) RG to compare relative expression levels of vSMCs in culture to those vSMCs within their physiological tissue environment. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Graphical abstract

19 pages, 7007 KiB  
Article
Impact of Short-Term (+)-JQ1 Exposure on Mouse Aorta: Unanticipated Inhibition of Smooth Muscle Contractility
by Binjie Yan, Yu Gui, Yanan Guo, Jiaxing Sun, Mahmoud Saifeddine, Jingti Deng, Joseph A. Hill, Morley D. Hollenberg, Zhi-Sheng Jiang and Xi-Long Zheng
Cells 2023, 12(11), 1461; https://doi.org/10.3390/cells12111461 - 24 May 2023
Cited by 3 | Viewed by 2778
Abstract
(+)-JQ1, a specific chemical inhibitor of bromodomain and extraterminal (BET) family protein 4 (BRD4), has been reported to inhibit smooth muscle cell (SMC) proliferation and mouse neointima formation via BRD4 regulation and modulate endothelial nitric oxide synthase (eNOS) activity. This study aimed to [...] Read more.
(+)-JQ1, a specific chemical inhibitor of bromodomain and extraterminal (BET) family protein 4 (BRD4), has been reported to inhibit smooth muscle cell (SMC) proliferation and mouse neointima formation via BRD4 regulation and modulate endothelial nitric oxide synthase (eNOS) activity. This study aimed to investigate the effects of (+)-JQ1 on smooth muscle contractility and the underlying mechanisms. Using wire myography, we discovered that (+)-JQ1 inhibited contractile responses in mouse aortas with or without functional endothelium, reducing myosin light chain 20 (LC20) phosphorylation and relying on extracellular Ca2+. In mouse aortas lacking functional endothelium, BRD4 knockout did not alter the inhibition of contractile responses by (+)-JQ1. In primary cultured SMCs, (+)-JQ1 inhibited Ca2+ influx. In aortas with intact endothelium, (+)-JQ1 inhibition of contractile responses was reversed by NOS inhibition (L-NAME) or guanylyl cyclase inhibition (ODQ) and by blocking the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. In cultured human umbilical vein endothelial cells (HUVECs), (+)-JQ1 rapidly activated AKT and eNOS, which was reversed by PI3K or ATK inhibition. Intraperitoneal injection of (+)-JQ1 reduced mouse systolic blood pressure, an effect blocked by co-treatment with L-NAME. Interestingly, (+)-JQ1 inhibition of aortic contractility and its activation of eNOS and AKT were mimicked by the (−)-JQ1 enantiomer, which is structurally incapable of inhibiting BET bromodomains. In summary, our data suggest that (+)-JQ1 directly inhibits smooth muscle contractility and indirectly activates the PI3K/AKT/eNOS cascade in endothelial cells; however, these effects appear unrelated to BET inhibition. We conclude that (+)-JQ1 exhibits an off-target effect on vascular contractility. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Figure 1

Review

Jump to: Research

20 pages, 1989 KiB  
Review
SWI/SNF Complex in Vascular Smooth Muscle Cells and Its Implications in Cardiovascular Pathologies
by Hongyu Liu, Yang Zhao, Guizhen Zhao, Yongjie Deng, Y. Eugene Chen and Jifeng Zhang
Cells 2024, 13(2), 168; https://doi.org/10.3390/cells13020168 - 16 Jan 2024
Cited by 3 | Viewed by 2666
Abstract
Mature vascular smooth muscle cells (VSMC) exhibit a remarkable degree of plasticity, a characteristic that has intrigued cardiovascular researchers for decades. Recently, it has become increasingly evident that the chromatin remodeler SWItch/Sucrose Non-Fermentable (SWI/SNF) complex plays a pivotal role in orchestrating chromatin conformation, [...] Read more.
Mature vascular smooth muscle cells (VSMC) exhibit a remarkable degree of plasticity, a characteristic that has intrigued cardiovascular researchers for decades. Recently, it has become increasingly evident that the chromatin remodeler SWItch/Sucrose Non-Fermentable (SWI/SNF) complex plays a pivotal role in orchestrating chromatin conformation, which is critical for gene regulation. In this review, we provide a summary of research related to the involvement of the SWI/SNF complexes in VSMC and cardiovascular diseases (CVD), integrating these discoveries into the current landscape of epigenetic and transcriptional regulation in VSMC. These novel discoveries shed light on our understanding of VSMC biology and pave the way for developing innovative therapeutic strategies in CVD treatment. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Figure 1

22 pages, 1362 KiB  
Review
Calcineurin Is a Universal Regulator of Vessel Function—Focus on Vascular Smooth Muscle Cells
by Alexander Nolze, Sebastian Matern and Claudia Grossmann
Cells 2023, 12(18), 2269; https://doi.org/10.3390/cells12182269 - 13 Sep 2023
Cited by 7 | Viewed by 2996
Abstract
Calcineurin, a serine/threonine phosphatase regulating transcription factors like NFaT and CREB, is well known for its immune modulatory effects and role in cardiac hypertrophy. Results from experiments with calcineurin knockout animals and calcineurin inhibitors indicate that calcineurin also plays a crucial role in [...] Read more.
Calcineurin, a serine/threonine phosphatase regulating transcription factors like NFaT and CREB, is well known for its immune modulatory effects and role in cardiac hypertrophy. Results from experiments with calcineurin knockout animals and calcineurin inhibitors indicate that calcineurin also plays a crucial role in vascular function, especially in vascular smooth muscle cells (VSMCs). In the aorta, calcineurin stimulates the proliferation and migration of VSMCs in response to vascular injury or angiotensin II administration, leading to pathological vessel wall thickening. In the heart, calcineurin mediates coronary artery formation and VSMC differentiation, which are crucial for proper heart development. In pulmonary VSMCs, calcineurin/NFaT signaling regulates the release of Ca2+, resulting in increased vascular tone followed by pulmonary arterial hypertension. In renal VSMCs, calcineurin regulates extracellular matrix secretion promoting fibrosis development. In the mesenteric and cerebral arteries, calcineurin mediates a phenotypic switch of VSMCs leading to altered cell function. Gaining deeper insights into the underlying mechanisms of calcineurin signaling will help researchers to understand developmental and pathogenetical aspects of the vasculature. In this review, we provide an overview of the physiological function and pathophysiology of calcineurin in the vascular system with a focus on vascular smooth muscle cells in different organs. Overall, there are indications that under certain pathological settings reduced calcineurin activity seems to be beneficial for cardiovascular health. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Figure 1

11 pages, 1279 KiB  
Review
The FAT1 Cadherin Drives Vascular Smooth Muscle Cell Migration
by Dario F. Riascos-Bernal, Gaia Ressa, Anish Korrapati and Nicholas E. S. Sibinga
Cells 2023, 12(12), 1621; https://doi.org/10.3390/cells12121621 - 14 Jun 2023
Cited by 6 | Viewed by 3199
Abstract
Vascular smooth muscle cells (VSMCs) are normally quiescent and non-migratory, regulating the contraction and relaxation of blood vessels to control the vascular tone. In response to arterial injury, these cells become active; they proliferate, secrete matrix proteins, and migrate, and thereby contribute importantly [...] Read more.
Vascular smooth muscle cells (VSMCs) are normally quiescent and non-migratory, regulating the contraction and relaxation of blood vessels to control the vascular tone. In response to arterial injury, these cells become active; they proliferate, secrete matrix proteins, and migrate, and thereby contribute importantly to the progression of several cardiovascular diseases. VSMC migration specifically supports atherosclerosis, restenosis after catheter-based intervention, transplant vasculopathy, and vascular remodeling during the formation of aneurysms. The atypical cadherin FAT1 is expressed robustly in activated VSMCs and promotes their migration. A positive role of FAT1 in the migration of other cell types, including neurons, fibroblasts, podocytes, and astrocyte progenitors, has also been described. In cancer biology, however, the effect of FAT1 on migration depends on the cancer type or context, as FAT1 either suppresses or enhances cancer cell migration and invasion. With this review, we describe what is known about FAT1’s effects on cell migration as well as the factors that influence FAT1-dependent migration. In VSMCs, these factors include angiotensin II, which activates FAT1 expression and cell migration, and proteins of the Atrophin family: Atrophin-1 and the short isoform of Atrophin-2, which promote VSMC migration, and the long isoform of Atrophin-2, which exerts negative effects on FAT1-dependent VSMC migration. Full article
(This article belongs to the Special Issue Role of Vascular Smooth Muscle Cells in Cardiovascular Disease)
Show Figures

Figure 1

Back to TopTop