Single-cell RNA-sequencing reaveals VSMC function in aortic disease
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PROVIDER: PRJNA863459 | ENA |
REPOSITORIES: ENA
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Project description:the regulation of gene expression in the murine determines the development of aortic disease.
2023-08-07 | GSE210024 | GEO
Project description:Myocardin (Myocd) plays an important role in the maintenance and homeostasis of the vasculature. The loss of Myocd results in vascular smooth muscle cell (VSMC) phenotypic transition and thoracic aortic aneurysms and dissections (TAADs) by downregulating VSMC contractile genes. VSMC phenotypic transition plays a key role in the formation of abdominal aortic aneurysms and dissections (AAADs). However, little is known about the role of Myocd in AAAD. The effect of Myocd on AAA formation was proven in an angiotensin II (Ang II)-induced AAD model. Myocd overexpression or knockdown was achieved by the injection of the corresponding adeno-associated virus serotype 9 (AAV9) through the tail vein. The knockdown of Myocd in C57BL/6J mice treated with angiotensin II promoted the formation of AAAD, as demonstrated by increases in the maximal aortic diameter, vascular inflammation and elastin degradation relative to the control group, while Myocd-overexpressing ApoE-/- mice infused with Ang II were less likely to develop AAAD. Mechanistically, Myocd deficiency significantly repressed VSMC marker gene expression. In addition, qPCR results showed that Myocd knockdown promoted the expression of lncRNAs, which showed increased levels in human AAD tissues. Our results indicated the pivotal role of Myocd in protecting against AAAD formation.
2024-10-25 | GSE180990 | GEO
Project description:Vascular stability and tone are maintained by contractile smooth muscle cells (VSMCs). However, injury-induced growth factors stimulate a contractile-synthetic phenotypic modulation which increases susceptibility to abdominal aortic aneurysm (AAA). As a regulator of embryonic VSMC differentiation, we hypothesised that Thymosin β4 (Tβ4) may function to maintain healthy vasculature throughout postnatal life. This was supported by the identification of an interaction with Low density lipoprotein receptor related protein 1 (LRP1), an endocytic regulator of PDGF-BB signalling and VSMC proliferation. LRP1 variants have been implicated by genome-wide association studies with risk of AAA and other arterial diseases. T4-null mice displayed aortic VSMC and elastin defects, phenocopying LRP1 mutants, and their compromised vascular integrity predisposed to Angiotensin II-induced aneurysm formation. Aneurysmal vessels were characterised by enhanced VSMC phenotypic modulation and augmented platelet-derived growth factor (PDGF) receptor (PDGFR)β signalling. In vitro, enhanced sensitivity to PDGF-BB, upon loss of Tβ4, associated with dysregulated endocytosis, with increased recycling and reduced lysosomal targeting of LRP1-PDGFRβ. Accordingly, the exacerbated aneurysmal phenotype in T4-null mice was rescued upon treatment with the PDGFRβ antagonist, Imatinib. Our study identifies Tβ4 as a key regulator of LRP1 for maintaining vascular health and provides insights into the mechanisms of growth factor-controlled VSMC phenotypic modulation underlying aortic disease progression.
2021-05-21 | PXD024162 | Pride
Project description:In current models of ascending aortic disease, mural cells undergo phenotypic changes that promote extracellular matrix destruction and structural weakening. To explore the intersection of this biology with quantitative trait GWAS loci we analyzed the genetic features of thoracic aortic aneurysm tissue. Single nuclear RNA sequencing was performed on 13 samples from human donors, 6 with thoracic aortic aneurysm and 7 without aneurysm. Individual transcriptomes were then clustered based on transcriptional profiles. Clusters were used for between-disease differential gene expression analyses, subcluster analysis, and analyzed for intersection with genetic aortic trait data. In total, we sequenced 71,689 nuclei from human thoracic aortas without aneurysm, and with sporadic aneurysm. We identified 14 clusters, aligning with 11 cell types, predominantly VSMCs, consistent with existing histologic data, but contrary to the majority of human aortic single cell studies to-date. With unbiased methodology, we found 7 VSMC and 6 fibroblast subclusters. Differentially expressed genes (DEGs) analysis revealed a VSMC group accounting for the majority of differential gene expression. Fibroblast populations in aneurysm exhibit distinct behavior with almost complete disappearance of quiescent fibroblasts. DEGs were used to prioritize genes at aortic diameter and distensibility GWAS loci highlighting the genes JUN, LTBP4, and IL34 in fibroblasts, ENTPD1, PDLIM5, ACTN4, and GLRX in VSMCs, as well as LRP1 in macrophage populations. In conclusion, using nuclear RNA sequencing we describe the cellular diversity of healthy and aneurysmal human ascending aorta. Sporadic aortic aneurysm is characterized by differential gene expression within known cellular classes rather than by the appearance of novel cellular forms. Single nuclear RNA sequencing of aortic tissue can be used to prioritize genes at aortic trait loci.
2022-10-03 | GSE207784 | GEO
Project description:Human VSMC isolates generated from aortic explants were treated in serum free media, +/- the addition of 500 ng / mL TIMP1 for 6 hours
2024-04-09 | GSE246647 | GEO
Project description:Myocardin Attenuates Aortic Aneurysm and Dissection Through the Maintenance of VSMC Homeostasis
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Project description:Hutchinson Gilford Progeria Syndrome is a premature aging disease caused by LMNA gene mutation and the production of a truncated lamin A protein “progerin” that elicits cellular and organismal toxicity. Progerin accumulates in the vasculature, being especially toxic for vascular smooth muscle cells (VSMC). Patients' autopsies show that vessel stiffening, and aortic atherosclerosis is accompanied by VSMC depletion in the medial layer, altered extracellular matrix (ECM), and thickening of the adventitial layer. Mechanisms whereby progerin causes massive VSMC loss and vessel alterations remain poorly understood. Mature VSMC retain phenotypic plasticity and can switch to a synthetic/proliferative phenotype. Here we show that progerin expression in human and mouse VSMC causes a switch towards the synthetic/proliferative phenotype. This switch elicits some level of replication stress in normal cells, which is exacerbated in the presence of progerin, leading to telomere fragility, genomic instability, and ultimately VSMC death. Importantly, calcitriol prevents replication stress, telomere fragility, and genomic instability, reducing VSMC death. In addition, RNAseq analysis shows induction of a profibrotic and proinflammatory aging-associated secretory phenotype upon progerin expression in human primary VSMC. Our data suggest that phenotypic switch-induced replication stress might be an underlying cause of VSMC loss in progeria, which together with loss of contractile features and gain of profibrotic and proinflammatory signatures contribute to vascular stiffness in HGPS. Preventing the phenotypic switch-induced replication stress with compounds such as calcitriol might ameliorate CVD in HGPS patients
2022-03-23 | GSE198983 | 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:Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of expression Sox9 has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism. 3 samples of aortic valve interstitial cells treated with DAPT were compared with 3 samples of aortic valve interstitial cells treated with DMSO
2011-08-25 | E-GEOD-31668 | biostudies-arrayexpress