Single-cell transcriptomic profiling of aortic cells from vascular smooth muscle cell-specific OPG-deficient mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE344971 | GEO | 2026/09/01
REPOSITORIES: GEO
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Project description:Cardiovascular diseases often manifest with vascular calcification. Vascular calcification is an active process orchestrated by contractile vascular smooth muscle cell (VSMC) phenotypic switch to an osteoblast-like cell. Here, we identified that the DNA demethylase, Tet2 (Ten-eleven translation 2), safeguards VSMCs from transitioning into the osteogenic lineage and loss of Tet2 promotes development and progression of vascular calcification. Tet2 was among the most significantly downregulated epigenetic markers in calcified aortas. VSMC-specific loss of Tet2 promoted VSMC osteogenic differentiation and enhanced vascular calcification as evidenced histologically, molecularly, and hemodynamically. In vivo studies further indicated that Tet2 inhibits calcification-associated VSMC apoptosis and medial thinning. Notably, calcified regions were enriched in a Trem2hi (triggered receptor expressed on myeloid cells 2) macrophage subpopulation. Intervention studies using high-dose ascorbate to enhance Tet2 enzymatic activity resulted in significantly reduced medial aortic calcification and improved aortic structural integrity in mice. Ascorbate treatment in human aorta organ cultures was sufficient to reduce calcification development in diseased tissues, and restore contractile properties to the calcified aorta. This study highlights the potential clinical impact of modulating Tet2 activity in managing cardiovascular disorders associated with vascular calcification.
2025-07-01 | GSE294266 | GEO
Project description:Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced polyubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhanced VC. HDAC1 protein, but not mRNA, was reduced in cell and animal calcification models and in human calcified coronary artery. In the calcification-provoking condition, proteasomal degradation of HDAC1 preceded VC. The calcification-provoking condition induced MDM2 E3 ligase, which then resulted in HDAC1 K74 polyubiquitination. Overexpression of MDM2 enhanced VC, whereas loss of MDM2 blunted it. Decoy peptides spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevented VC in vivo and in vitro. These results demonstrate a previously unknown ubiquitination pathway and suggest MDM2-mediated HDAC1 polyubiquitination as a new therapeutic target in VC. Calcification was induced in rat aorta vascular smooth muscle cells with inorganic phosphate (Pi). Total RNA were extracted from the cells 3 and 6 days later. mRNA profile of the sample was compared with normal control.
2015-11-07 | E-GEOD-74755 | biostudies-arrayexpress
Project description:Recent evidence has shown a crucial role for the osteoprotegerin/receptor activator of nuclear factor κ-B ligand/RANK (OPG/RANKL/RANK) signaling axis not only in bone but also in muscle tissue; however, there is still a lack of understanding of its effects on muscle atrophy. Here, we found that denervated Opg knockout mice displayed better functional recovery and delayed muscle atrophy, especially in a specific type IIB fiber. Moreover, OPG deficiency promoted milder activation of the ubiquitin-proteasome pathway, which further verified the protective role of Opg knockout in denervated muscle damage. Furthermore, transcriptome sequencing indicated that Opg knockout upregulated the expression of Inpp5k, Rbm3, and Tet2 and downregulated that of Deptor in denervated muscle. In vitro experiments revealed that satellite cells derived from Opg knockout mice displayed a better differentiation ability than those acquired from wild-type littermates. Higher expression levels of Tet2 were also observed in satellite cells derived from Opg knockout mice, which provided a mechanistic basis for the protective effects of Opg knockout on muscle atrophy. Taken together, our findings uncover the novel role of Opg in muscle atrophy process and extend the current understanding in the OPG/RANKL/RANK signaling axis.
2023-05-01 | GSE220152 | GEO
Project description:Cardiovascular calcification can occur in vascular and valvular structures and is commonly associated with calcium deposition and tissue mineralization leading to stiffness and dysfunction. Based on shared risk factors and end stage pathologies, calcific aortic valve disease (CAVD) and coronary artery calcification (CAC) are often considered as one disease, and similarly treated. However, the clinical conditions associated with each phenotype can be different, suggesting multifaceted pathologies. To better understand diversity in molecular and cellular processes that underlie calcification in vascular and valvular structures, we exposed aortic vascular smooth muscle cells (AVSMCs) and aortic valve interstitial cells (AVICs) to calcific stimuli including high (2.5mM) phosphate and osteogenic media (OM) treatments in vitro. Consistent with clinical observations made by others, we show that AVSMCs are more susceptible to calcification than AVICs, and this process is mediated by cell-specific and treatment-specific molecular responses. RNA-seq analysis demonstrates that in response to calcific-stimuli, both AVSMCs and AVICs activate a robust ossification-program, although the signaling pathways, cellular processes and osteogenic-associated markers involved are diverse. In addition, VIC-mediated calcification appears to involve biological processes related to osteo-chondro differentiation and down regulation of actin cytoskeleton genes, that are not observed in VSMCs. Furthermore, are findings suggest that signaling pathways involved in cardiovascular cell calcification are dependent on the calcific-stimuli, including a requirement of PI3K signaling for OM-induced calcification, and not 2.5mM Phosphate. Together, this study provides a wealth of information suggesting that the pathogenesis of cardiovascular calcifications may be significantly more diverse than previously appreciated.
2023-08-01 | GSE227131 | GEO
Project description:Vascular calcification is a hallmark of atherosclerosis and end-stage renal disease (ESRD). However, the molecular mechanism of vascular calcification is poorly understood. Diabetes mellitus is increasingly recognized as the most important cause for atherosclerosis and ESRD. Emerging evidence supports the concept that vascular calcification resembles the process of osteogenesis, in which the vascular smooth muscle cells (VSMC) undergo osteochondrogenic differentiation. Recently, we have established an in vitro calcification system with primary mouse VSMC. With the use of osteogenic stimuli, we induced trans-differentiation of primary mouse VSMC into bone-like cells. Interestingly stroptozotocin (STZ), O-GlcNAcase inhibitor and a drug that has been used to induce diabetes in mice, was able to induce calcification of VSMC and the expression of the osteogenic transcription factor Runx2, suggesting glycosylation may be involved in regulation of Runx2. We have reported an essential role of Runx2 in oxidative stress-induce VSMC calcification and have recently generated a tissue specific mouse with Runx2 ablation in smooth muscle cells. Therefore, we will use STZ and other relevant reagents in the glucose synthesis/metabolism pathways as stimuli for VSMC calcification to characterize the glycogene profiles during VSMC calcification. Results from VSMC of Runx2 knockout mice will be compared with those from control mice to determine the regulation of calcification-associated glycogenes by Runx2 in response to STZ. These studies will provide foundation for further mechanistic studies and may lead to identification of novel strategies and targets for diabetes-induced vascular calcification. To examine vascular smooth muscle cells (VSMC) under two conditions: 1) wild-type VSMC differentiated into bone-like cells with osteogenic media, 2) wild-type VSMC treated with STZ and osteogenic media
2011-09-05 | E-GEOD-31928 | biostudies-arrayexpress
Project description:This study aimed to identify small molecules that inhibit vascular calcification with computational approach. To examine the mechanism of calcification inhibition, proteomics analysis was performed using aorta tissue samples to clarify therapeutic target.
2022-02-17 | PXD029963 | Pride
Project description:Single-cell transcriptomic profiling of aortic cells from vascular smooth muscle cell-specific OPG-deficient mice
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Project description:Uremic media calcification is not only driven by systemic factors such as hyperphosphatemia, but also crticially dependent on vascular smooth muscle cells per se. We hypothesized that the different developmental origins of vscular smooth muscle cells might lead to a heterogeneous susceptibility to develop media calcification. Upon high-phosphate diet, the transcriptional profile revealed an induction of an inflammatory vascular smooth muscle phenotype only in the abdominal, but not in the thoracic aorta. Thus, smooth muscle cells from different lineages responded differently to morphogenetic cues in vivo. We analyzed 3-4 replicates of the thoracic and abdominal aorta, which were previously exposed to either high-phosphate diet (HPD) or standard chow diet (SCD), respectively.
2014-05-26 | E-GEOD-57818 | biostudies-arrayexpress
Project description:In this study, we identified various cell clusters in human normal/sporadic TAA ascending aorta samples by single-cell RNA sequencing (scRNA-seq), and discovered the senescent vascular smooth muscle cells (VSMCs) significantly increased in TAA samples. Then we explored the molecular basis of TAA progression, and recognized the key regulators and pathways involved in the TAA progression regulation.
2023-12-01 | GSE143921 | GEO
Project description:Metastasis is the major cause of cancer-related mortality. In the lung metastasis, monocyte-derived macrophages (Mo-macs) exhibit a complex function. However, tumor cells how to derive lung metastasis through Mo-macs remains unclear. Here we show that a tumor-secreted protein osteoprotegerin (OPG) contributes to the lung metastasis of cancer depends on the Mo-macs by an in vivo screening. OPG binds with RANKL to block the signaling between RANKL-RANK on Mo-macs. RANKL-RANK signals induce Mo-macs to secrete CXCL10, recruiting NK cells to control the lung metastasis. Increased expression of OPG in the metastases is regulated by TGF-β. Consistent with our findings, enrichment of OPG amplifications was observed in metastatic cancer patients, and increased expression of OPG was also shown in the lung metastatic sites compared with the paired primary breast cancer samples. Overall, our findings reveal a mechanism of how tumor cells promote lung metastasis via inhibiting the function of Mo-macs.
2024-12-16 | GSE259293 | GEO