International Journal of Molecular Sciences

Research

14 pages, 1098 KiB

Open AccessArticle

Role of SGK1 in the Osteogenic Transdifferentiation and Calcification of Vascular Smooth Muscle Cells Promoted by Hyperglycemic Conditions

by Florian Poetsch, Laura A. Henze, Misael Estepa, Barbara Moser, Burkert Pieske, Florian Lang, Kai-Uwe Eckardt, Ioana Alesutan and Jakob Voelkl

Int. J. Mol. Sci. 2020, 21(19), 7207; https://doi.org/10.3390/ijms21197207 - 29 Sep 2020

Cited by 19 | Viewed by 2671

Abstract

In diabetes mellitus, hyperglycemia promotes the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) to enhance medial vascular calcification, a common complication strongly associated with cardiovascular disease and mortality. The mechanisms involved are, however, still poorly understood. Therefore, the present study explored the [...] Read more.

In diabetes mellitus, hyperglycemia promotes the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) to enhance medial vascular calcification, a common complication strongly associated with cardiovascular disease and mortality. The mechanisms involved are, however, still poorly understood. Therefore, the present study explored the potential role of serum- and glucocorticoid-inducible kinase 1 (SGK1) during vascular calcification promoted by hyperglycemic conditions. Exposure to high-glucose conditions up-regulated the SGK1 expression in primary human aortic VSMCs. High glucose increased osteogenic marker expression and activity and, thus, promoted the osteogenic transdifferentiation of VSMCs, effects significantly suppressed by additional treatment with the SGK1 inhibitor EMD638683. Moreover, high glucose augmented the mineralization of VSMCs in the presence of calcification medium, effects again significantly reduced by SGK1 inhibition. Similarly, SGK1 knockdown blunted the high glucose-induced osteogenic transdifferentiation of VSMCs. The osteoinductive signaling promoted by high glucose required SGK1-dependent NF-κB activation. In addition, advanced glycation end products (AGEs) increased the SGK1 expression in VSMCs, and SGK1 inhibition was able to interfere with AGEs-induced osteogenic signaling. In conclusion, SGK1 is up-regulated and mediates, at least partly, the osteogenic transdifferentiation and calcification of VSMCs during hyperglycemic conditions. Thus, SGK1 inhibition may reduce the development of vascular calcification promoted by hyperglycemia in diabetes. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

11 pages, 2336 KiB

Open AccessArticle

The Metabolism of Epoxyeicosatrienoic Acids by Soluble Epoxide Hydrolase Is Protective against the Development of Vascular Calcification

by Olivier Varennes, Romuald Mentaverri, Thomas Duflot, Gilles Kauffenstein, Thibaut Objois, Gaëlle Lenglet, Carine Avondo, Christophe Morisseau, Michel Brazier, Saïd Kamel, Isabelle Six and Jeremy Bellien

Int. J. Mol. Sci. 2020, 21(12), 4313; https://doi.org/10.3390/ijms21124313 - 17 Jun 2020

Cited by 6 | Viewed by 2591

Abstract

This study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes endothelium-derived epoxyeicosatrienoic acids, plays a role in vascular calcification. The sEH inhibitor trans-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (t-AUCB) potentiated the increase in calcium deposition of rat aortic rings cultured in high-phosphate [...] Read more.

This study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes endothelium-derived epoxyeicosatrienoic acids, plays a role in vascular calcification. The sEH inhibitor trans-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (t-AUCB) potentiated the increase in calcium deposition of rat aortic rings cultured in high-phosphate conditions. This was associated with increased tissue-nonspecific alkaline phosphatase activity and mRNA expression level of the osteochondrogenic marker Runx2. The procalcifying effect of t-AUCB was prevented by mechanical aortic deendothelialization or inhibition of the production and action of epoxyeicosatrienoic acids using the cytochrome P450 inhibitor fluconazole and the antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), respectively. Similarly, exogenous epoxyeicosatrienoic acids potentiated the calcification of rat aortic rings through a protein kinase A (PKA)-dependent mechanism and of human aortic vascular smooth muscle cells when sEH was inhibited by t-AUCB. Finally, a global gene expression profiling analysis revealed that the mRNA expression level of sEH was decreased in human carotid calcified plaques compared to adjacent lesion-free sites and was inversely correlated with Runx2 expression. These results show that sEH hydrolase plays a protective role against vascular calcification by reducing the bioavailability of epoxyeicosatrienoic acids. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

15 pages, 5280 KiB

Open AccessArticle

Therapeutic Effect of Iron Citrate in Blocking Calcium Deposition in High Pi-Calcified VSMC: Role of Autophagy and Apoptosis

by Paola Ciceri, Monica Falleni, Delfina Tosi, Carla Martinelli, Stefania Cannizzo, Giulia Marchetti, Antonella D’Arminio Monforte, Gaetano Bulfamante, Geoffrey A Block, Piergiorgio Messa and Mario Cozzolino

Int. J. Mol. Sci. 2019, 20(23), 5925; https://doi.org/10.3390/ijms20235925 - 25 Nov 2019

Cited by 23 | Viewed by 3787

Abstract

In chronic kidney disease (CKD), the first cause of mortality is cardiovascular disease induced mainly by vascular calcification (VC). Recently, iron-based phosphate binders have been proposed in advanced CKD to treat hyperphosphatemia. We studied the effect of iron citrate (iron) on the progression [...] Read more.

In chronic kidney disease (CKD), the first cause of mortality is cardiovascular disease induced mainly by vascular calcification (VC). Recently, iron-based phosphate binders have been proposed in advanced CKD to treat hyperphosphatemia. We studied the effect of iron citrate (iron) on the progression of calcification in high-phosphate (Pi) calcified VSMC. Iron arrested further calcification when added on days 7–15 in the presence of high Pi (1.30 ± 0.03 vs 0.61 ± 0.02; OD/mg protein; day 15; Pi vs Pi + Fe, p < 0.01). We next investigated apoptosis and autophagy. Adding iron to high-Pi-treated VSMC, on days 7–11, decreased apoptotic cell number (17.3 ± 2.6 vs 11.6 ± 1.6; Annexin V; % positive cells; day 11; Pi vs Pi + Fe; p < 0.05). The result was confirmed thorough analysis of apoptotic nuclei both in VSMCs and aortic rings treated on days 7–15 (3.8 ± 0.2 vs 2.3 ± 0.3 and 4.0 ± 0.3 vs 2.2 ± 0.2; apoptotic nuclei; arbitrary score; day 15; Pi vs Pi + Fe; VSMCs and aortic rings; p < 0.05). Studying the prosurvival axis GAS6/AXL, we found that iron treatment on days 9–14 counteracted protein high-Pi-stimulated down-regulation and induced its de novo synthesis. Moreover, iron added on days 9–15 potentiated autophagy, as detected by an increased number of autophagosomes with damaged mitochondria and an increase in autophagic flux. Highlighting the effect of iron on apoptosis, we demonstrated its action in blocking the H₂O₂-induced increase in calcification added both before high Pi treatment and when the calcification was already exacerbated. In conclusion, we demonstrate that iron arrests further high Pi-induced calcium deposition through an anti-apoptotic action and the induction of autophagy on established calcified VSMC. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

Review

Jump to: Research, Other

27 pages, 3809 KiB

Open AccessReview

X-ray Micro-Computed Tomography: An Emerging Technology to Analyze Vascular Calcification in Animal Models

by Samantha J. Borland, Julia Behnsen, Nick Ashton, Sheila E. Francis, Keith Brennan, Michael J. Sherratt, Philip J. Withers and Ann E. Canfield

Int. J. Mol. Sci. 2020, 21(12), 4538; https://doi.org/10.3390/ijms21124538 - 25 Jun 2020

Cited by 13 | Viewed by 4828

Abstract

Vascular calcification describes the formation of mineralized tissue within the blood vessel wall, and it is highly associated with increased cardiovascular morbidity and mortality in patients with chronic kidney disease, diabetes, and atherosclerosis. In this article, we briefly review different rodent models used [...] Read more.

Vascular calcification describes the formation of mineralized tissue within the blood vessel wall, and it is highly associated with increased cardiovascular morbidity and mortality in patients with chronic kidney disease, diabetes, and atherosclerosis. In this article, we briefly review different rodent models used to study vascular calcification in vivo, and critically assess the strengths and weaknesses of the current techniques used to analyze and quantify calcification in these models, namely 2-D histology and the o-cresolphthalein assay. In light of this, we examine X-ray micro-computed tomography (µCT) as an emerging complementary tool for the analysis of vascular calcification in animal models. We demonstrate that this non-destructive technique allows us to simultaneously quantify and localize calcification in an intact vessel in 3-D, and we consider recent advances in µCT sample preparation techniques. This review also discusses the potential to combine 3-D µCT analyses with subsequent 2-D histological, immunohistochemical, and proteomic approaches in correlative microscopy workflows to obtain rich, multifaceted information on calcification volume, calcification load, and signaling mechanisms from within the same arterial segment. In conclusion we briefly discuss the potential use of µCT to visualize and measure vascular calcification in vivo in real-time. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

24 pages, 1255 KiB

Open AccessReview

Roles of Histone Acetylation Modifiers and Other Epigenetic Regulators in Vascular Calcification

by Duk-Hwa Kwon, Juhee Ryu, Young-Kook Kim and Hyun Kook

Int. J. Mol. Sci. 2020, 21(9), 3246; https://doi.org/10.3390/ijms21093246 - 4 May 2020

Cited by 18 | Viewed by 4017

Abstract

Vascular calcification (VC) is characterized by calcium deposition inside arteries and is closely associated with the morbidity and mortality of atherosclerosis, chronic kidney disease, diabetes, and other cardiovascular diseases (CVDs). VC is now widely known to be an active process occurring in vascular [...] Read more.

Vascular calcification (VC) is characterized by calcium deposition inside arteries and is closely associated with the morbidity and mortality of atherosclerosis, chronic kidney disease, diabetes, and other cardiovascular diseases (CVDs). VC is now widely known to be an active process occurring in vascular smooth muscle cells (VSMCs) involving multiple mechanisms and factors. These mechanisms share features with the process of bone formation, since the phenotype switching from the contractile to the osteochondrogenic phenotype also occurs in VSMCs during VC. In addition, VC can be regulated by epigenetic factors, including DNA methylation, histone modification, and noncoding RNAs. Although VC is commonly observed in patients with chronic kidney disease and CVD, specific drugs for VC have not been developed. Thus, discovering novel therapeutic targets may be necessary. In this review, we summarize the current experimental evidence regarding the role of epigenetic regulators including histone deacetylases and propose the therapeutic implication of these regulators in the treatment of VC. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

20 pages, 2550 KiB

Open AccessReview

The Role of Sclerostin in Bone and Ectopic Calcification

by Annelies De Maré, Patrick C. D’Haese and Anja Verhulst

Int. J. Mol. Sci. 2020, 21(9), 3199; https://doi.org/10.3390/ijms21093199 - 30 Apr 2020

Cited by 31 | Viewed by 5930

Abstract

Sclerostin, a 22-kDa glycoprotein that is mainly secreted by the osteocytes, is a soluble inhibitor of canonical Wnt signaling. Therefore, when present at increased concentrations, it leads to an increased bone resorption and decreased bone formation. Serum sclerostin levels are known to be [...] Read more.

Sclerostin, a 22-kDa glycoprotein that is mainly secreted by the osteocytes, is a soluble inhibitor of canonical Wnt signaling. Therefore, when present at increased concentrations, it leads to an increased bone resorption and decreased bone formation. Serum sclerostin levels are known to be increased in the elderly and in patients with chronic kidney disease. In these patient populations, there is a high incidence of ectopic cardiovascular calcification. These calcifications are strongly associated with cardiovascular morbidity and mortality. Although data are still controversial, it is likely that there is a link between ectopic calcification and serum sclerostin levels. The main question, however, remains whether sclerostin exerts either a protective or deleterious role in the ectopic calcification process. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

32 pages, 1698 KiB

Open AccessReview

Vascular Calcification—New Insights into Its Mechanism

by Sun Joo Lee, In-Kyu Lee and Jae-Han Jeon

Int. J. Mol. Sci. 2020, 21(8), 2685; https://doi.org/10.3390/ijms21082685 - 13 Apr 2020

Cited by 256 | Viewed by 15880

Abstract

Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few [...] Read more.

Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

21 pages, 1015 KiB

Open AccessReview

The Role of Vitamin D in Modulating Mesenchymal Stem Cells and Endothelial Progenitor Cells for Vascular Calcification

by Yi-Chou Hou, Chien-Lin Lu, Cai-Mei Zheng, Wen-Chih Liu, Tzung-Hai Yen, Ruei-Ming Chen, Yuh-Feng Lin, Chia-Ter Chao and Kuo-Cheng Lu

Int. J. Mol. Sci. 2020, 21(7), 2466; https://doi.org/10.3390/ijms21072466 - 2 Apr 2020

Cited by 22 | Viewed by 5256

Abstract

Vascular calcification, which involves the deposition of calcifying particles within the arterial wall, is mediated by atherosclerosis, vascular smooth muscle cell osteoblastic changes, adventitial mesenchymal stem cell osteoblastic differentiation, and insufficiency of the calcification inhibitors. Recent observations implied a role for mesenchymal stem [...] Read more.

Vascular calcification, which involves the deposition of calcifying particles within the arterial wall, is mediated by atherosclerosis, vascular smooth muscle cell osteoblastic changes, adventitial mesenchymal stem cell osteoblastic differentiation, and insufficiency of the calcification inhibitors. Recent observations implied a role for mesenchymal stem cells and endothelial progenitor cells in vascular calcification. Mesenchymal stem cells reside in the bone marrow and the adventitial layer of arteries. Endothelial progenitor cells that originate from the bone marrow are an important mechanism for repairing injured endothelial cells. Mesenchymal stem cells may differentiate osteogenically by inflammation or by specific stimuli, which can activate calcification. However, the bioactive substances secreted from mesenchymal stem cells have been shown to mitigate vascular calcification by suppressing inflammation, bone morphogenetic protein 2, and the Wingless-INT signal. Vitamin D deficiency may contribute to vascular calcification. Vitamin D supplement has been used to modulate the osteoblastic differentiation of mesenchymal stem cells and to lessen vascular injury by stimulating adhesion and migration of endothelial progenitor cells. This narrative review clarifies the role of mesenchymal stem cells and the possible role of vitamin D in the mechanisms of vascular calcification. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

15 pages, 474 KiB

Open AccessReview

Novel Insight into Neuroimmune Regulatory Mechanisms and Biomarkers Linking Major Depression and Vascular Diseases: The Dilemma Continues

by Ingrid Tonhajzerova, Nikola Sekaninova, Lucia Bona Olexova and Zuzana Visnovcova

Int. J. Mol. Sci. 2020, 21(7), 2317; https://doi.org/10.3390/ijms21072317 - 27 Mar 2020

Cited by 30 | Viewed by 4096

Abstract

Major depressive disorder (MDD) represents a serious health problem estimated to affect 350 million people globally. Importantly, MDD has repeatedly emerged as an etiological or prognostic factor in cardiovascular disease (CVD) development, including vascular pathology. Several linking pathomechanisms between MDD and CVD involve [...] Read more.

Major depressive disorder (MDD) represents a serious health problem estimated to affect 350 million people globally. Importantly, MDD has repeatedly emerged as an etiological or prognostic factor in cardiovascular disease (CVD) development, including vascular pathology. Several linking pathomechanisms between MDD and CVD involve abnormal autonomic regulation, inflammation, and endothelial dysfunction as an early preclinical stage of atherosclerosis. However, the cause of accelerated atherosclerosis in MDD patients remains unclear. Recently, the causal relationships between MDD and mediator (e.g., inflammation and/or endothelial dysfunction), as well as the causal pathways from the mediator to atherosclerosis, were discussed. Specifically, MDD is accompanied by immune dysregulation, resulting in increased production of proinflammatory cytokines (e.g., interleukin (IL)-6 and tumor necrosis factor (TNF)-α), which could lead to depression-linked abnormalities in brain function. Further, MDD has an adverse effect on endothelial function; for example, circulating markers of endothelial dysfunction (e.g., soluble adhesion molecules, von Willebrand factor) have been linked with depression. Additionally, MDD-linked autonomic dysregulation, which is characterized by disrupted sympathovagal balance associated with excessive circulating catecholamines, can contribute to CVD. Taken together, activated inflammatory response, endothelial dysfunction, and autonomic dysregulation could affect gradual atherosclerosis progression, resulting in a higher risk of developing CVD in MDD. This review focused on the pathomechanisms linking MDD and CVD with respect to neuroimmune regulation, and the description of promising biomarkers, which is important for the early diagnosis and personalized prevention of CVD in major depression. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

23 pages, 1708 KiB

Open AccessReview

Research Models for Studying Vascular Calcification

by Jaqueline Herrmann, Milen Babic, Markus Tölle, Markus van der Giet and Mirjam Schuchardt

Int. J. Mol. Sci. 2020, 21(6), 2204; https://doi.org/10.3390/ijms21062204 - 23 Mar 2020

Cited by 41 | Viewed by 6985

Abstract

Calcification of the vessel wall contributes to high cardiovascular morbidity and mortality. Vascular calcification (VC) is a systemic disease with multifaceted contributing and inhibiting factors in an actively regulated process. The exact underlying mechanisms are not fully elucidated and reliable treatment options are [...] Read more.

Calcification of the vessel wall contributes to high cardiovascular morbidity and mortality. Vascular calcification (VC) is a systemic disease with multifaceted contributing and inhibiting factors in an actively regulated process. The exact underlying mechanisms are not fully elucidated and reliable treatment options are lacking. Due to the complex pathophysiology, various research models exist evaluating different aspects of VC. This review aims to give an overview of the cell and animal models used so far to study the molecular processes of VC. Here, in vitro cell culture models of different origins, ex vivo settings using aortic tissue and various in vivo disease-induced animal models are summarized. They reflect different aspects and depict the (patho)physiologic mechanisms within the VC process. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

19 pages, 1594 KiB

Open AccessReview

Sirtuin-1 and Its Relevance in Vascular Calcification

by Chien-Lin Lu, Min-Tser Liao, Yi-Chou Hou, Yu-Wei Fang, Cai-Mei Zheng, Wen-Chih Liu, Chia-Ter Chao, Kuo-Cheng Lu and Yee-Yung Ng

Int. J. Mol. Sci. 2020, 21(5), 1593; https://doi.org/10.3390/ijms21051593 - 26 Feb 2020

Cited by 44 | Viewed by 8041

Abstract

Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that [...] Read more.

Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of β-catenin that, following the facilitation of β-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

20 pages, 1604 KiB

Open AccessReview

The Epigenetic Landscape of Vascular Calcification: An Integrative Perspective

by Yi-Chou Hou, Chien-Lin Lu, Tzu-Hang Yuan, Min-Tser Liao, Chia-Ter Chao and Kuo-Cheng Lu

Int. J. Mol. Sci. 2020, 21(3), 980; https://doi.org/10.3390/ijms21030980 - 1 Feb 2020

Cited by 34 | Viewed by 4380

Abstract

Vascular calcification (VC) is an important complication among patients of advanced age, those with chronic kidney disease, and those with diabetes mellitus. The pathophysiology of VC encompasses passive occurrence of physico-chemical calcium deposition, active cellular secretion of osteoid matrix upon exposure to metabolically [...] Read more.

Vascular calcification (VC) is an important complication among patients of advanced age, those with chronic kidney disease, and those with diabetes mellitus. The pathophysiology of VC encompasses passive occurrence of physico-chemical calcium deposition, active cellular secretion of osteoid matrix upon exposure to metabolically noxious stimuli, or a variable combination of both processes. Epigenetic alterations have been shown to participate in this complex environment, through mechanisms including DNA methylation, non-coding RNAs, histone modifications, and chromatin changes. Despite such importance, existing reviews fail to provide a comprehensive view of all relevant reports addressing epigenetic processes in VC, and cross-talk between different epigenetic machineries is rarely examined. We conducted a systematic review based on PUBMED and MEDLINE databases up to 30 September 2019, to identify clinical, translational, and experimental reports addressing epigenetic processes in VC; we retrieved 66 original studies, among which 60.6% looked into the pathogenic role of non-coding RNA, followed by DNA methylation (12.1%), histone modification (9.1%), and chromatin changes (4.5%). Nine (13.6%) reports examined the discrepancy of epigenetic signatures between subjects or tissues with and without VC, supporting their applicability as biomarkers. Assisted by bioinformatic analyses blending in each epigenetic component, we discovered prominent interactions between microRNAs, DNA methylation, and histone modification regarding potential influences on VC risk. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

29 pages, 1546 KiB

Open AccessReview

The Role of Vascular Smooth Muscle Cells in Arterial Remodeling: Focus on Calcification-Related Processes

by Armand Jaminon, Koen Reesink, Abraham Kroon and Leon Schurgers

Int. J. Mol. Sci. 2019, 20(22), 5694; https://doi.org/10.3390/ijms20225694 - 14 Nov 2019

Cited by 180 | Viewed by 13005

Abstract

Arterial remodeling refers to the structural and functional changes of the vessel wall that occur in response to disease, injury, or aging. Vascular smooth muscle cells (VSMC) play a pivotal role in regulating the remodeling processes of the vessel wall. Phenotypic switching of [...] Read more.

Arterial remodeling refers to the structural and functional changes of the vessel wall that occur in response to disease, injury, or aging. Vascular smooth muscle cells (VSMC) play a pivotal role in regulating the remodeling processes of the vessel wall. Phenotypic switching of VSMC involves oxidative stress-induced extracellular vesicle release, driving calcification processes. The VSMC phenotype is relevant to plaque initiation, development and stability, whereas, in the media, the VSMC phenotype is important in maintaining tissue elasticity, wall stress homeostasis and vessel stiffness. Clinically, assessment of arterial remodeling is a challenge; particularly distinguishing intimal and medial involvement, and their contributions to vessel wall remodeling. The limitations pertain to imaging resolution and sensitivity, so methodological development is focused on improving those. Moreover, the integration of data across the microscopic (i.e., cell-tissue) and macroscopic (i.e., vessel-system) scale for correct interpretation is innately challenging, because of the multiple biophysical and biochemical factors involved. In the present review, we describe the arterial remodeling processes that govern arterial stiffening, atherosclerosis and calcification, with a particular focus on VSMC phenotypic switching. Additionally, we review clinically applicable methodologies to assess arterial remodeling and the latest developments in these, seeking to unravel the ubiquitous corroborator of vascular pathology that calcification appears to be. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Graphical abstract

Other

Jump to: Research, Review

12 pages, 11655 KiB

Open AccessTechnical Note

A Novel Protocol for Detection of Senescence and Calcification Markers by Fluorescence Microscopy

by Jaqueline Herrmann, Milen Babic, Markus Tölle, Kai-Uwe Eckardt, Markus van der Giet and Mirjam Schuchardt

Int. J. Mol. Sci. 2020, 21(10), 3475; https://doi.org/10.3390/ijms21103475 - 14 May 2020

Cited by 9 | Viewed by 3874

Abstract

Vascular calcification and stiffening of the arterial wall is a systemic phenomenon that is associated with aging and it can be increased by several risk factors. The underlying mechanisms, especially the pathways of cellular senescence, are under current investigation. Easily manageable in vitro [...] Read more.

Vascular calcification and stiffening of the arterial wall is a systemic phenomenon that is associated with aging and it can be increased by several risk factors. The underlying mechanisms, especially the pathways of cellular senescence, are under current investigation. Easily manageable in vitro settings help to study the signaling pathways. The experimental setting presented here is based on an in vitro model using rat vascular smooth muscle cells and the detection of senescence and osteoblastic markers via immunofluorescence and RNAscope™. Co-staining of the senescence marker p21, the osteoblastic marker osteopontin, detection of senescence-associated heterochromatin foci, and senescence-associated β-galactosidase is possible within one test approach requiring fewer cells. The protocol is a fast and reliable evaluation method for multiplexing of calcifying and senescence markers with fluorescence microscopy detection. The experimental setting enables analysis on single cell basis and allows detection of intra-individual variances of cultured cells. Full article

(This article belongs to the Special Issue Mechanisms of Vascular Calcification)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Mechanisms of Vascular Calcification

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (14 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI