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14 pages, 2565 KiB

Open AccessArticle

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 - 09 Apr 2024

Viewed by 533

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)

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20 pages, 8275 KiB

Open AccessArticle

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 1 | Viewed by 1223

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)

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21 pages, 4862 KiB

Open AccessArticle

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 2935

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)

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17 pages, 7093 KiB

Open AccessArticle

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

Viewed by 1018

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)

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19 pages, 7007 KiB

Open AccessArticle

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 1550

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)

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20 pages, 1989 KiB

Open AccessReview

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

Viewed by 1046

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)

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22 pages, 1362 KiB

Open AccessReview

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

Viewed by 1272

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)

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11 pages, 1279 KiB

Open AccessReview

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 2 | Viewed by 1839

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)

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