Inflammation and the osteogenic regulation of vascular calcification: a review and perspective.
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ABSTRACT:
SUBMITTER: Shao JS
PROVIDER: S-EPMC2853014 | biostudies-literature | 2010 Mar
REPOSITORIES: biostudies-literature
Publications
Inflammation and the osteogenic regulation of vascular calcification: a review and perspective.
Shao Jian-Su JS Cheng Su-Li SL Sadhu Justin J Towler Dwight A DA
Hypertension (Dallas, Tex. : 1979) 20100125 3
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Project description:Vascular calcification (VC) is highly correlated with cardiovascular disease morbidity and mortality, but anti-VC treatment remains an area to be tackled due to the ill-defined molecular mechanisms. Regardless of the type of VC, it does not depend on a single cell but involves multi-cells/organs to form a complex cellular communication network through the vascular microenvironment to participate in the occurrence and development of VC. Therefore, focusing only on the direct effect of pathological factors on vascular smooth muscle cells (VSMCs) tends to overlook the combined effect of other cells and VSMCs, including VSMCs-VSMCs, ECs-VMSCs, Macrophages-VSMCs, etc. Extracellular vesicles (EVs) are a collective term for tiny vesicles with a membrane structure that are actively secreted by cells, and almost all cells secrete EVs. EVs docked on the surface of receptor cells can directly mediate signal transduction or transfer their contents into the cell to elicit a functional response from the receptor cells. They have been proven to participate in the VC process and have also shown attractive therapeutic prospects. Based on the advantages of EVs and the ability to be detected in body fluids, they may become a novel therapeutic agent, drug delivery vehicle, diagnostic and prognostic biomarker, and potential therapeutic target in the future. This review focuses on the new insight into VC molecular mechanisms from the perspective of crosstalk, summarizes how multi-cells/organs interactions communicate via EVs to regulate VC and the emerging potential of EVs as therapeutic methods in VC. We also summarize preclinical experiments on crosstalk-based and the current state of clinical studies on VC-related measures.
| S-EPMC10584806 | biostudies-literature
Project description:RationaleVascular calcification is a prominent feature of late-stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in patients reported that plasma levels of osteomodulin (OMD), a proteoglycan involved in bone mineralisation, associate with diabetes and CVD. We hypothesised that OMD could be implicated in these diseases via vascular calcification as a common underlying factor and aimed to investigate its role in this context.Methods and resultsIn patients with chronic kidney disease, plasma OMD levels correlated with markers of inflammation and bone turnover, with the protein present in calcified arterial media. Plasma OMD also associated with cardiac calcification and the protein was detected in calcified valve leaflets by immunohistochemistry. In patients with carotid atherosclerosis, circulating OMD was increased in association with plaque calcification as assessed by computed tomography. Transcriptomic and proteomic data showed that OMD was upregulated in atherosclerotic compared to control arteries, particularly in calcified plaques, where OMD expression correlated positively with markers of smooth muscle cells (SMCs), osteoblasts and glycoproteins. Immunostaining confirmed that OMD was abundantly present in calcified plaques, localised to extracellular matrix and regions rich in α-SMA+ cells. In vivo, OMD was enriched in SMCs around calcified nodules in aortic media of nephrectomised rats and in plaques from ApoE-/- mice on warfarin. In vitro experiments revealed that OMD mRNA was upregulated in SMCs stimulated with IFNγ, BMP2, TGFβ1, phosphate and β-glycerophosphate, and by administration of recombinant human OMD protein (rhOMD). Mechanistically, addition of rhOMD repressed the calcification process of SMCs treated with phosphate by maintaining their contractile phenotype along with enriched matrix organisation, thereby attenuating SMC osteoblastic transformation. Mechanistically, the role of OMD is exerted likely through its link with SMAD3 and TGFB1 signalling, and interplay with BMP2 in vascular tissues.ConclusionWe report a consistent association of both circulating and tissue OMD levels with cardiovascular calcification, highlighting the potential of OMD as a clinical biomarker. OMD was localised in medial and intimal α-SMA+ regions of calcified cardiovascular tissues, induced by pro-inflammatory and pro-osteogenic stimuli, while the presence of OMD in extracellular environment attenuated SMC calcification.
| S-EPMC8858609 | biostudies-literature
Project description: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.
| S-EPMC7037112 | biostudies-literature
Project description:Vascular calcification is the ectopic deposition of calcium hydroxyapatite minerals in arterial wall, which involves the transdifferentiation of vascular smooth muscle cells (VSMCs) toward an osteogenic phenotype. However, the underlying molecular mechanisms regulating the VSMC osteogenic switch remain incompletely understood. In this study, we examined the roles of microRNAs (miRNAs) in vascular calcification. miRNA-seq transcriptome analysis identified miR-223-3p as a candidate miRNA in calcified mouse aortas. MiR-223-3p knockout aggravated calcification in both medial and atherosclerotic vascular calcification models. Further, RNA-seq transcriptome analysis verified JAK-STAT and PPAR signaling pathways were upregulated in both medial and atherosclerotic calcified aortas. Overlapping genes in these signaling pathways with predicted target genes of miR-223-3p derived from miRNA databases, we identified signal transducer and activator of transcription 3 (STAT3) as a potential target gene of miR-223-3p in vascular calcification. In vitro experiments showed that miR-223-3p blocked interleukin-6 (IL-6)/STAT3 signaling, thereby preventing the osteogenic switch and calcification of VSMCs. In contrast, overexpression of STAT3 diminished the effect of miR-223-3p. Taken together, the results indicate a protective role of miR-223-3p that inhibits both medial and atherosclerotic vascular calcification by regulating IL-6/STAT3 signaling-mediated VSMC transdifferentiation.
| S-EPMC8039724 | biostudies-literature
Project description:Vascular calcification (VC) is a common pathological change in many chronic diseases, such as diabetes and chronic kidney disease. It is mainly deposited in the intima and media of vessels in the form of hydroxyapatite. Recently, a lot of research has been performed to show that VC is associated with various cellular stresses, such as hyperphosphate, hyperglycemia and oxidative stress. Unfortunately, our understanding of the pathogenesis of calcification is far from comprehensive. Sirtuins belong to a family of class III highly conserved deacetylases that are involved in the regulation of biological and cellular processes including mitochondrial biogenesis, metabolism, oxidative stress, inflammatory response, DNA repair, etc. Numerous studies have shown that sirtuins might play protective roles in VC, and restoring the activity of sirtuins may be a potentially effective treatment for VC. However, the exact mechanism of their vascular protection remains unclear. Here, we reviewed the roles of sirtuins in the osteogenic transformation of vascular smooth muscle cells and the development of VC. We also elucidated the applications of sirtuins agonists for the treatment of VC.
| S-EPMC9198215 | biostudies-literature
Project description:Vascular calcification is an actively regulated process that culminates in organized extracellular matrix mineral deposition by osteoblast-like cells. The origins of the osteoblastic cells involved in this process and the underlying mechanisms remain to be defined. We previously revealed that active transforming growth factor (TGF?) released from the injured arteries mobilizes mesenchymal stem cells (MSCs) to the blood stream and recruits the cells to the injured vessels for neointima formation. In this study, we used a low-density lipoprotein receptor (LDLR)-deficient mouse model (ldlr(-/-)), which develop progressive arterial calcification after having fed high-fat western diets (HFD), to examine whether TGF? is involved in the mobilization of MSCs during vascular calcification. Nestin(+)/Sca1(+) cells were recruited to the diseased aorta at earlier time points, and osteocalcin(+) osteoblasts and the aortic calcification were seen at later time point in these mice. Importantly, we generated parabiotic pairs with shared blood circulation by crossing ldlr(-/-)mice fed HFD with transgenic mice, in which all the MSC-derived cells were fluorescently labeled. The labeled cells were detected not only in the peripheral blood but also in the arterial lesions in ldlr(-/-) mouse partners, and these blood circulation-originated cells gave rise to Ocn(+) osteoblastic cells at the arterial lesions. Both active TGF?1 levels and MSCs in circulating blood were upregulated at the same time points when these cells appeared at the aortic tissue. Further, conditioned medium prepared by incubating the aortae from ldlr(-/-)mice fed HFD stimulated the migration of MSCs in the ex vivo transwell assays, and either TGF? neutralizing antibody or the inhibitor of TGF? Receptor I kinase (T?RI) antagonized this effect. Importantly, treatment of the mice with T?RI inhibitor blocked elevated blood MSC numbers and their recruitment to the arterial lesions. These findings suggest that TGF?-recruited MSCs to the diseased vasculature contribute to the development of osteogenic vascular calcification.
| S-EPMC4046215 | biostudies-literature
Project description:SGLT-2 inhibitors, such as empagliflozin, have been shown to reduce the occurrence of cardiovascular events and delay the progression of atherosclerosis. However, its role in atherosclerotic calcification remains unclear. In this research, ApoE-/- mice were fed with western diet and empagliflozin was added to the drinking water for 24 weeks. Empagliflozin treatment significantly alleviated arterial calcification assessed by alizarin red and von kossa staining in aortic roots and reduced the lipid levels, while had little effect on body weight and blood glucose levels in ApoE-/- mice. In vitro studies, empagliflozin significantly inhibits calcification of primary vascular smooth muscle cells (VSMCs) and aortic rings induced by osteogenic media (OM) or inorganic phosphorus (Pi). RNA sequencing of VSMCs cultured in OM with or without empagliflozin showed that empagliflozin negatively regulated the osteogenic differentiation of VSMCs. And further studies confirmed that empagliflozin significantly inhibited osteogenic differentiation of VSMCs via qRT-PCR. Our study demonstrates that empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of VSMCs, which addressed a critical need for the discovery of a drug-based therapeutic approach in the treatment of atherosclerotic calcification.
| S-EPMC10716287 | biostudies-literature
Project description:Vascular calcification (VC) arises from the accumulation of calcium salts in the intimal or tunica media layer of the aorta, contributing to higher risk of cardiovascular events and mortality. Despite this, the mechanisms driving VC remain incompletely understood. We previously described that nesfatin-1 functioned as a switch for vascular smooth muscle cells (VSMCs) plasticity in hypertension and neointimal hyperplasia. In this study, we sought to investigate the role and mechanism of nesfatin-1 in VC. The expression of nesfatin-1 was measured in calcified VSMCs and aortas, as well as in patients. Loss- and gain-of-function experiments were evaluated the roles of nesfatin-1 in VC pathogenesis. The transcription activation of nesfatin-1 was detected using a mass spectrometry. We found higher levels of nesfatin-1 in both calcified VSMCs and aortas, as well as in patients with coronary calcification. Loss-of-function and gain-of-function experiments revealed that nesfatin-1 was a key regulator of VC by facilitating the osteogenic transformation of VSMCs. Mechanistically, nesfatin-1 promoted the de-ubiquitination and stability of BMP-2 via inhibiting the E3 ligase SYTL4, and the interaction of nesfatin-1 with BMP-2 potentiated BMP-2 signaling and induced phosphorylation of Smad, followed by HDAC4 phosphorylation and nuclear exclusion. The dissociation of HDAC4 from RUNX2 elicited RUNX2 acetylation and subsequent nuclear translocation, leading to the transcription upregulation of OPN, a critical player in VC. From a small library of natural compounds, we identified that Curculigoside and Chebulagic acid reduced VC development via binding to and inhibiting nesfatin-1. Eventually, we designed a mass spectrometry-based DNA-protein interaction screening to identify that STAT3 mediated the transcription activation of nesfatin-1 in the context of VC. Overall, our study demonstrates that nesfatin-1 enhances BMP-2 signaling by inhibiting the E3 ligase SYTL4, thereby stabilizing BMP-2 and facilitating the downstream phosphorylation of SMAD1/5/9 and HDAC4. This signaling cascade leads to RUNX2 activation and the transcriptional upregulation of MSX2, driving VC. These insights position nesfatin-1 as a potential therapeutic target for preventing or treating VC, advancing our understanding of the molecular mechanisms underlying this critical cardiovascular condition.
| S-EPMC11468037 | biostudies-literature
Project description:Calcification is a prominent feature of late-stage atherosclerosis, but the mechanisms driving this process are unclear. Using a biobank of carotid endarterectomies, we recently showed that Proteoglycan 4 (PRG4) is a key molecular signature of calcified plaques, expressed in smooth muscle cell (SMC) rich regions. Here, we aimed to unravel the PRG4 role in vascular remodeling and intimal calcification. PRG4 expression in human carotid endarterectomies correlated with calcification assessed by preoperative computed tomographies. PRG4 localized to SMCs in early intimal thickening, while in advanced lesions it was found in the extracellular matrix, surrounding macro-calcifications. In experimental models, Prg4 was upregulated in SMCs from partially ligated ApoE-/- mice and rat carotid intimal hyperplasia, correlating with osteogenic markers and TGFb1. Furthermore, PRG4 was enriched in cells positive for chondrogenic marker SOX9 and around plaque calcifications in ApoE-/- mice on warfarin. In vitro, PRG4 was induced in SMCs by IFNg, TGFb1 and calcifying medium, while SMC markers were repressed under calcifying conditions. Silencing experiments showed that PRG4 expression was driven by transcription factors SMAD3 and SOX9. Functionally, the addition of recombinant human PRG4 increased ectopic SMC calcification, while arresting cell migration and proliferation. Mechanistically, it suppressed endogenous PRG4, SMAD3 and SOX9, and restored SMC markers' expression. PRG4 modulates SMC function and osteogenic phenotype during intimal remodeling and macro-calcification in response to TGFb1 signaling, SMAD3 and SOX9 activation. The effects of PRG4 on SMC phenotype and calcification suggest its role in atherosclerotic plaque stability, warranting further investigations.
| S-EPMC8224064 | biostudies-literature
Project description:Vascular calcification is a severe pathological event in the manifestation of atherosclerosis. Pathogenic triggers mediating osteogenic differentiation of arterial smooth muscle cells (SMC) in humans remain insufficiently understood and are to a large extent investigated in animal models or cells derived thereof. Here, we describe an in vitro model based on SMC derived from healthy and diseased humans that allows to comprehensively investigate vascular calcification mechanisms. Comparing the impact of the commonly used SMC culture media VascuLife, DMEM, and M199, cells were characterised by immunofluorescence, flow cytometry, qPCR, and regarding their contractility and proliferative capacity. Irrespective of the arterial origin, the clinical background and the expansion medium used, all cells expressed typical molecular SMC marker while contractility varied between donors. Interestingly, the ability to induce an osteogenic differentiation strongly depended on the culture medium, with only SMC cultured in DMEM depositing calcified matrix upon osteogenic stimulation, which correlated with increased alkaline phosphatase activity, increased inorganic phosphate level and upregulation of osteogenic gene markers. Our optimized model is suitable for donor-oriented as well as broader screening of potential pathogenic mediators triggering vascular calcification. Translational studies aiming to identify and to evaluate therapeutic targets in a personalized fashion would be feasible.
| S-EPMC7136202 | biostudies-literature