Transcriptional changes upon overexpression of seven candidate miRNAs in human saphenous vein smooth muscle cells. [HSVSMC]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE253003 | GEO | 2025/01/10
REPOSITORIES: GEO
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Project description:Proliferation of vascular smooth muscle cells (vSMCs) following injury is a crucial factor contributing to pathological vascular remodelling. MicroRNAs (miRNAs) are powerful gene regulators and attractive therapeutics agents. Here, we aim to systemically identify and characterise miRNAs with therapeutic potential in targeting aberrant vSMC proliferation. We performed a high-throughput in vitro screen using a library of 2042 human miRNA-mimics for their impact on VSMC proliferation and identified seven novel antiproliferative miRNAs i.e miR-1827, miR-4774-3p, miR-5681b, miR-449b-5p, miR-491-3p, miR-323a-3p, and miR-892b.Overexpression of these 7 miRNAs affects proliferation of vSMCs from different vascular beds. Focusing on vein graft failure, a condition in which miRNA based therapeutics can be applied to the graft ex-vivo, we showed that these miRNAs reduced human saphenous vein SMC (HSVSMC) proliferation without inducing apoptosis or senescence, and five of them also significantly decreased migration.In contrast to HSVSMC, miRNA overexpression on saphenous vein endothelial cells (ECs) led to no or lower decrease of proliferation for the seven miRNAs. We performed RNA-seq on HSVEC overexpressing the seven miRNAs and showed a limited response of ECs to the miRNA overexpression.
2025-01-10 | GSE253002 | GEO
Project description:Rationale: microRNAs (miRNAs) modulate gene expression by repressing translation of targeted genes. Previous work has established a role for miRNAs in regulating vascular smooth muscle cell (VSMC) activity. Whether circular RNAs (circRNA) are involved in the modulation of miRNA activity in VSMCs is unknown. Objective: We aimed to identify circRNAs interacting with miRNAs enriched in VSMCs and modulating the cells' activity. Methods and Results: RNA sequencing and bioinformatics identified several circRNAs enriched in VSMCs; however, only one, possessing multiple putative binding sites for miR-145, was highly conserved between mouse and man. This circRNA gemmed from alternative splicing of lipoprotein receptor 6 (Lrp6), a gene highly expressed in vessels and implicated in vascular pathologies, and was thus named circ_Lrp6. Its role as a miR-145 sponge was confirmed by determining reciprocal interaction through RNA immunoprecipitation, stimulated emission depletion microscopy, and competitive luciferase assays; functional inhibition of miR-145 was assessed by measuring expression of the target genes ITGβ8, FASCIN, KLF4, Yes1, and Lox. The interaction was preferentially localized to P-bodies, sites of mRNA degradation. Using loss- and gain-of-function approaches, we found that circ_Lrp6 hindered miR-145-mediated regulation of VSMC migration, proliferation, and differentiation. Differential expression of miR-145 and circ_Lrp6 in murine and human vascular diseases suggests that the ratio of circ_Lrp6 bound to miR145 vs. unbound could play a role in vascular pathogenesis. Viral delivery of circ_Lrp6 shRNA prevented intimal hyperplasia in mouse carotids. Conclusions: circ_Lrp6 is an intracellular modulator and a natural sponge for miR-145, counterbalancing the functions of the miRNA in VSMCs.
2018-12-05 | GSE99318 | GEO
Project description:MiRNAs regulate posttranscriptional gene expression and are widely implicated in the pathogenesis of complex diseases. We aim to elucidate miRNA regulation of the atrial mRNA signatures that associate with AF. This may provide novel mechanistical insights and candidate targets for therapies using miRNA mimics or antimiRs.
We present combined miRNAs-mRNAs sequencing in atrial tissues of patient without AF (n=22), with paroxysmal AF (n=22) and with persistent AF (n=20). MiRNA and mRNA signatures followed an ordinal scale from nonAF to paroxysmal to persistent AF patients. The previously reported mRNA sequencing identified 5228 differentially expressed genes involved in epithelial to mesenchymal transition, endothelial cell proliferation and extracellular matrix remodelling involving collagens, glycoproteins and proteoglycans. We discovered 103 differentially expressed miRNAs. Key downregulated miRNAs included miR-135b-5p, miR-138-5p, miR-200a-3p, miR-200b-3p and miR-31-5p and key upregulated miRNAs were miR-144-3p, miR-15b-3p, miR-182-5p miR-18b-5p, miR-4306 and miR-206. The expression levels of differentially expressed miRNAs were negatively correlated with the expression levels of their predicted target mRNAs. The downregulated miRNAs demonstrated a more profound transcriptome effect than the upregulated miRNAs. Upregulated biological processes enriched in miRNAs targets related to epithelial and endothelial cell migration and glycosaminoglycan biosynthesis, in line with the processes discovered by the mRNA sequencing analysis.
Combined analysis of miRNA and mRNA sequencing uncovered miRNAs with a broad transcriptional effect in human AF. Epithelial to mesenchymal transition and endothelial cell proliferation were processes controlled by downregulated miR-135b-5p, miR-138-5p, miR-200a-3p, miR-200b-3p and miR-31-5p, which in turn may contribute to (myo)fibroblast activation and structural remodeling.\
| EGAS00001005296 | EGA
Project description:The proliferation and remodeling of vascular smooth muscle cells (VSMCs) is an important pathological event in atherosclerosis and restenosis. Here we report that microRNA-132 (miR-132) blocks vascular smooth muscle cells (VSMC) proliferation by inhibiting the expression of LRRFIP1 [leucine-rich repeat (in Flightless 1) interacting protein-1]. MicroRNA microarray revealed that miR-132 was upregulated in the rat carotid artery after catheter injury, which was further confirmed by quantitative real-time RT-PCR. Transfection of an miR-132 mimic significantly inhibited the proliferation of VSMCs, whereas transfection of an miR-132 antagomir increased it. Bioinformatics showed that LRRFIP1 is a target candidate of miR-132. miR-132 down-regulated luciferase activity driven by a vector containing the 3’-untranslated region of Lrrfip1 in a sequence-specific manner. LRRFIP1 induced VSMC proliferation. Immunohistochemical analysis revealed that Lrrfip1 was clearly expressed along with the basal laminar area of smooth muscle, and its expression pattern was disrupted 7 days after arterial injury LRRFIP1 mRNA was decreased 14 days after injury. Delivery of miR-132 to rat carotid artery attenuated neointimal proliferation in carotid artery injury models. Our results suggest that miR-132 is a novel regulator of VSMC proliferation that represses neointimal formation by inhibiting LRRFIP1 expression. Balloon injury was induced in the carotid arteries of male Sprague–Dawley rats weighing approximately 250 g. Total RNA were extracted from the arterial sections after 10 days. MicroRNA profile of the sample was compared with non-injured control.
2013-04-23 | E-GEOD-45433 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression by negatively regulating translation of target genes. miRNAs involvement in vascular smooth muscle cell (VSMC) biology has been deeply investigated, nevertheless the role of miR-128 in such context has not been yet explored. We aimed to evaluate whether this miR-128 might modulate VSMC phenotype similarly to what was previously observed for other type of contractile cells, such as cardiomyocytes (CM) and skeletal muscle cells. To this end, we compared the expression profiles of miR-128 overexpression in Primary mouse VSMCs and control groups (treated with scrambled miRNA). The expression profiles were defined by Illumina arrays.
2020-09-07 | GSE124764 | GEO
Project description:Vascular smooth muscle cell (VSMC) dysregulation is a hallmark of vascular disease, including atherosclerosis. In particular, the majority of cells within atherosclerotic lesions are generated from pre-existing VSMCs and a clonal nature has been documented for VSMC-derived cells in multiple disease models. However, the mechanisms underlying the generation of oligoclonal lesions and the phenotype of proliferating VSMCs are unknown.Here we analyse clonal dynamics in multi-color lineage-traced animals over time after vessel injury to understand the cellular mechanisms underlying clonal VSMC expansion in disease.We demonstrate that VSMC proliferation is initiated in a small fraction of VSMCs that initially expand clonally in the medial layer and then migrate to form the oligoclonal neointima. Selective activation of VSMC proliferation also occurs in vitro, suggesting that this is a cell-autonomous feature. Mapping of VSMC trajectories using single-cell RNA-sequencing reveals a continuum of cellular states after injury and suggests that VSMC proliferation initiates in cells that have downregulated the contractile phenotype and show evidence of pronounced phenotypic switching. We show that proliferation is associated with induced expression of stem cell antigen 1 (SCA1) and the expression signature previously identified in SCA1+ VSMCs in healthy arteries. A remarkably increased proliferation of SCA1+ VSMCs, directly validated in functional assays, indicates that SCA1+ VSMCs act as "first responders" in vascular injury. Early atherosclerotic lesions also had clonal VSMC contribution and we show that the proliferation-associated injury response is conserved in plaque VSMCs, extending these findings to atherosclerosis. Finally, we identify VSMCs in healthy human arteries that correspond to the SCA1+ state in mouse VSMCs and show that genes identified as differentially expressed in this human VSMC subpopulation are enriched for genes showing genetic association with cardiovascular disease. We show that cell-intrinsic, selective VSMC activation drives clonal proliferation after injury and in atherosclerosis. Our study suggests that healthy mouse and human arteries contain VSMCs characterised by expression of disease-associated genes that are predisposed for proliferation. Targeting such "first responder" cells in patients undergoing vascular surgery could effectively prevent injury-associated VSMC activation and neoatherosclerosis.
2022-08-25 | GSE162167 | GEO
Project description:The proliferation and remodeling of vascular smooth muscle cells (VSMCs) is an important pathological event in atherosclerosis and restenosis. Here we report that microRNA-132 (miR-132) blocks vascular smooth muscle cells (VSMC) proliferation by inhibiting the expression of LRRFIP1 [leucine-rich repeat (in Flightless 1) interacting protein-1]. MicroRNA microarray revealed that miR-132 was upregulated in the rat carotid artery after catheter injury, which was further confirmed by quantitative real-time RT-PCR. Transfection of an miR-132 mimic significantly inhibited the proliferation of VSMCs, whereas transfection of an miR-132 antagomir increased it. Bioinformatics showed that LRRFIP1 is a target candidate of miR-132. miR-132 down-regulated luciferase activity driven by a vector containing the 3’-untranslated region of Lrrfip1 in a sequence-specific manner. LRRFIP1 induced VSMC proliferation. Immunohistochemical analysis revealed that Lrrfip1 was clearly expressed along with the basal laminar area of smooth muscle, and its expression pattern was disrupted 7 days after arterial injury LRRFIP1 mRNA was decreased 14 days after injury. Delivery of miR-132 to rat carotid artery attenuated neointimal proliferation in carotid artery injury models. Our results suggest that miR-132 is a novel regulator of VSMC proliferation that represses neointimal formation by inhibiting LRRFIP1 expression.
2013-04-23 | GSE45433 | GEO
Project description:iPSC-derived neurons were treated with mimics and inhibitors of the miRNAs miR-150-5p, hsa-mir-193a-3p and hsa-miR-19b-3p.
RNA-sequencing was then performed to examine the effects of miRNA up-regulation and inhibition.
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Project description:Adult vascular smooth muscle cells (VSMCs) dedifferentiate in response to extracellular cues such as vascular damage and inflammation. Dedifferentiated VSMCs are proliferative, migratory, less contractile, and can contribute to vascular repair as well as to cardiovascular pathologies such as intimal hyperplasia/restenosis in coronary artery and arterial aneurysm. We here demonstrate the role of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) as an epigenetic master regulator of VSMC plasticity. UHRF1 expression correlated with the development of vascular pathologies associated with modulation of noncoding RNAs, such as microRNAs. miR-145 — pivotal in regulating VSMC plasticity, which is reduced in vascular diseases — was found to control Uhrf1 mRNA translation. In turn, UHRF1 triggered VSMC proliferation, directly repressing promoters of cell-cycle inhibitor genes (including p21 and p27) and key prodifferentiation genes via the methylation of DNA and histones. Local vascular viral delivery of Uhrf1 shRNAs or Uhrf1 VSMC-specific deletion prevented intimal hyperplasia in mouse carotid artery and decreased vessel damage in a mouse model of aortic aneurysm. Our study demonstrates the fundamental role of Uhrf1 in regulating VSMC phenotype by promoting proliferation and dedifferentiation. UHRF1 targeting may hold therapeutic potential in vascular pathologies.
2018-12-05 | GSE99472 | GEO
Project description:Diabetes promotes pro-atherogenic and pro-inflammatory phenotype of VSMC associated with vascular complications. Emerging evidence shows that miRNAs play key roles in VSMC, but their role in diabetes induced effects is unclear. We profiled novel diabetes induced miRNAs in VSMC from diabetic mice and examined their role in VSMC dysfunction. High throughput small RNA-sequencing identified 135 differentially expressed miRNAs in VSMC from type 2 diabetic db/db mice (db/dbVSMC) versus non-diabetic db/+ mice. Several of these miRNA were known to regulate VSMC functions. We further focused on miR-504, because it was highly upregulated in db/dbVSMC, but its function in VSMC is unknown. We demonstrated that miR-504 and its host gene Fgf13 were upregulated in VSMC and in vivo in aortas from db/db mice. Bioinformatics analysis predicted that miR-504 targets, including a signaling adaptor Grb10 and a transcription factor Egr2, could regulate growth factor signaling. We experimentally verified that miR-504 targets Grb10 and Egr2, and it enhanced ERK1/2 activation, proliferation and migration in VSMC. Silencing Grb10 by small interfering RNA also enhanced ERK1/2 activation, inflammatory gene expression and migration. Whereas, Egr2 silencing downregulated anti-inflammatory SOCS1 and increased inflammatory genes. Furthermore, treatment with high-glucose and palmitic acid upregulated miR-504, inhibited Grb10 and enhanced inflammatory genes in VSMC. Diabetes mis-regulates expression of several miRNAs including miR-504 involved in VSMC functions. Changes in miRNAs are sustained in non-diabetic conditions suggesting involvement of miRNA dependent mechanisms in metabolic memory implicated in vascular complications. Targeting such mechanisms could offer novel therapies strategies.
2016-04-15 | GSE74521 | GEO