RNA sequencing of aortic tissues from Prdm16 smooth muscle-specific KO and control mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE227692 | GEO | 2026/06/03
REPOSITORIES: GEO
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Project description:Abdominal aortic aneurysm (AAA) is usually asymptomatic until life-threatening complications occur, predominantly involving aortic rupture. Currently, no drug-based treatments are available, primarily due to limited understanding of AAA pathogenesis. The transcriptional regulator PR domain–containing protein 16 (PRDM16) is highly expressed in the aorta, but its functions in the aorta are largely unknown. By RNA-seq analysis, we found that vascular smooth muscle cell–specific (VSMC-specific) Prdm16-knockout (Prdm16SMKO) mice already showed extensive changes in the expression of genes associated with extracellular matrix (ECM) remodeling and inflammation in the abdominal aorta under normal housing conditions without any pathological stimuli. Human AAA lesions displayed lower PRDM16 expression. Periadventitial elastase application to the suprarenal region of the abdominal aorta aggravated AAA formation in Prdm16SMKO mice. During AAA development, VSMCs undergo apoptosis because of both intrinsic and environmental changes, including inflammation and ECM remodeling. Prdm16 deficiency promoted inflammation and apoptosis in VSMCs. A disintegrin and metalloproteinase 12 (ADAM12) is a gelatinase that can degrade various ECMs. We found that ADAM12 is a target of transcriptional repression by PRDM16. Adam12 knockdown reversed VSMC apoptosis induced by Prdm16 deficiency. Our study demonstrated that PRDM16 deficiency in VSMCs promoted ADAM12 expression and aggravates AAA formation, which may provide potential targets for AAA treatment.
2023-06-08 | GSE222440 | GEO
Project description:BACKGROUND: Vascular smooth muscle cells (VSMC) are the most abundant cell type in the artery’s media layer and regulate vascular tone and lesion remodeling during atherogenesis. Like monocyte-derived macrophages, VSMCs accumulate excess lipids and contribute to the total intimal foam cell population in human coronary plaque and mouse aortic atheroma. While there are extensive studies characterizing the contribution of lipid metabolism in macrophage immunometabolic responses in atherosclerotic plaques, the role of VSMC lipid metabolism in regulating vascular function and lesion remodeling in vivo remains poorly understood. METHODS: We re-analyzed publicly available single-cell RNA sequencing (scRNA-seq) data from mouse atherosclerosis studies and found Liver X receptor (LXR) signaling in VSMCs was continuously activated during atherogenesis. We thus generated mice with an inducible SMC-specific knockout of LXR/LXR on a fate mapping background by crossbreeding LXRf/fLXRf/f mice with Myh11-CreERT2;mTmGf/f mice. Mice were administered with tamoxifen (1 mg/day) for 10 consecutive days and followed by a 2-week resting period to induce CreERT2 mediated recombination. To induce hypercholesterolemia and atherosclerosis, we injected Myh11-CreERT2;mT/mGf/f;LXRf/fLXRf/f mice and Myh11-CreERT2;mT/mGf/f mice with AAV8-PCSK9 and fed them with a Western diet (WD) for 16 weeks. Metabolic, immunocytochemistry and genomic analysis were conducted to assess lesion size and morphology and unravel the molecular mechanism by which LXR in VSMC contributes to lesion formation. RESULTS: Deficiency of LXR in SMCs under hypercholesterolemic condition influenced lesion remodeling by altering the fate of de-differentiated SMC and promoting the accumulation of VSMC-derived transitional cells. This phenotypic switching is accompanied with reduced index of plaque stability characterized by larger necrotic core area and reduced fibrous cap thickness. Moreover, SMC-specific LXR deficiency impaired vascular function and caused visceral myopathy characterized by bladder maladaptive remodeling and gut lipid malabsorption. CONCLUSIONS: We unveil an essential role of hypercholesterolemia-induced LXR signaling in atherosclerotic lesion remodeling, controlling the fate decision of VSMCs and regulating vascular and visceral SMCs functions.
2025-03-03 | GSE269449 | GEO
Project description:Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce a variety of cell phenotypes in response to pathologic stimuli. In atherosclerosis, these phenotypically modulated SMCs play a critical role in determining plaque composition and the risk of major adverse cardiovascular events. We found that PRDM16, a transcription factor that has been genetically implicated in cardiovascular disease, is highly expressed in arterial SMCs, and downregulated during SMC fate switching in human and mouse atherosclerosis. Deletion of Prdm16 in SMCs of mice activates the synthetic modulation program in arteries under homeostatic conditions. Upon exposure to atherogenic conditions, these mice form strikingly dense, SMC-rich, fibroproliferative plaques that contain few foam cells. Acute deletion of Prdm16 in SMCs triggers a similar fibrotic response, resulting in the formation of collagen-rich lesions with thick fibrous caps – a hallmark of enhanced lesion stability. Reciprocally, ectopic expression of PRDM16 in cultured cells is sufficient to block SMC synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, our results define PRDM16 as a specific gatekeeper of the synthetic SMC switch and reveal that PRDM16 levels in SMCs predetermine atherogenic lesion composition.
2025-08-28 | GSE305275 | GEO
Project description:Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce a variety of cell phenotypes in response to pathologic stimuli. In atherosclerosis, these phenotypically modulated SMCs play a critical role in determining plaque composition and the risk of major adverse cardiovascular events. We found that PRDM16, a transcription factor that has been genetically implicated in cardiovascular disease, is highly expressed in arterial SMCs, and downregulated during SMC fate switching in human and mouse atherosclerosis. Deletion of Prdm16 in SMCs of mice activates the synthetic modulation program in arteries under homeostatic conditions. Upon exposure to atherogenic conditions, these mice form strikingly dense, SMC-rich, fibroproliferative plaques that contain few foam cells. Acute deletion of Prdm16 in SMCs triggers a similar fibrotic response, resulting in the formation of collagen-rich lesions with thick fibrous caps – a hallmark of enhanced lesion stability. Reciprocally, ectopic expression of PRDM16 in cultured cells is sufficient to block SMC synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, our results define PRDM16 as a specific gatekeeper of the synthetic SMC switch and reveal that PRDM16 levels in SMCs predetermine atherogenic lesion composition.
2025-08-28 | GSE305272 | GEO
Project description:Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce a variety of cell phenotypes in response to pathologic stimuli. In atherosclerosis, these phenotypically modulated SMCs play a critical role in determining plaque composition and the risk of major adverse cardiovascular events. We found that PRDM16, a transcription factor that has been genetically implicated in cardiovascular disease, is highly expressed in arterial SMCs, and downregulated during SMC fate switching in human and mouse atherosclerosis. Deletion of Prdm16 in SMCs of mice activates the synthetic modulation program in arteries under homeostatic conditions. Upon exposure to atherogenic conditions, these mice form strikingly dense, SMC-rich, fibroproliferative plaques that contain few foam cells. Acute deletion of Prdm16 in SMCs triggers a similar fibrotic response, resulting in the formation of collagen-rich lesions with thick fibrous caps – a hallmark of enhanced lesion stability. Reciprocally, ectopic expression of PRDM16 in cultured cells is sufficient to block SMC synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, our results define PRDM16 as a specific gatekeeper of the synthetic SMC switch and reveal that PRDM16 levels in SMCs predetermine atherogenic lesion composition.
2025-08-28 | GSE305277 | GEO
Project description:We sought to identify microRNAs that were differentially regulated in cultured primary human aortic smooth muscle cells (SMCs) when exposed to growth arrest via serum starvation over two time points - 48 hours and 72 hours, when compared with serum-fed cells. This treatment leads to increased expression of SMC differentiation markers such as ACTA2, MYH11 and TAGLN. We identified 31 significantly regulated miRNA candidates during this process, 28 rising and 3 falling. Human aortic SMCs (AoSMCs) were propagated in growth media. Control plates were harvested, and the remaining plates were serum starved for 48 (SS48) or 72 hours (SS72) in serum-free basal media. Several arrays were excluded from final analysis after QC, resulting in a final set of 10.
2009-12-25 | E-GEOD-19544 | biostudies-arrayexpress
Project description:The LIM-only protein FHL2 is expressed in SMCs and inhibits SMC-rich lesion formation. However, the underlying mechanism behind FHL2's action in SMCs has been only partially resolved. To further elucidate the role of FHL2 in SMCs we compared the transcriptome of cultured SMCs derived from wild-type (WT) and FHL2-knockout (KO) mice. Comparison of gene expression in aortic smooth muscle cells (SMCs) isolated from WT and FHL2-knockout (FHL2-KO) mice. SMCs isolated from three mouse aortas were pooled (Kurakula et al, PLOS One, 2014). Both for WT and FHL-KO mice three batches of SMCs (derived from 9 mice) were cultured. The SMCs were grown to confluency and maintained in serum-free medium for 48 hrs before harvest. Subsequently, RNA was isolated for gene expression profiling.
2014-10-07 | E-GEOD-56860 | biostudies-arrayexpress
Project description:The multiple claims about reactivation of the embryonic stem cell (ESC) pluripotency factor OCT4 in somatic cells are highly controversial due to the fact that there is no direct evidence that OCT4 has a functional role in cells other than ESCs. Herein we demonstrate that smooth muscle cell (SMC)-specific knockout of Oct4 within atherosclerotic mice resulted in increased lesion size and multiple changes consistent with decreased plaque stability. SMC-lineage tracing studies showed that lesions from SMC-specific conditional Oct4 KO mice had a reduced number of SMCs likely due to impaired SMC migration. RNA-seq analysis of lesion specimens showed that loss of Oct4 in SMCs was associated with marked activation of genes associated with inflammation and suppression of genes associated with cell migration, a number of which were shown to be activated in cultured SMCs by the combination of hypoxia and oxidized phospholipids in an OCT4-dependent manner. Activation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was HIF1α- and KLF4-dependent. Results provide the first genetic evidence that OCT4 plays a functional role in somatic cells and highlight the importance of further investigation of possible OCT4 functions in somatic cells. In vivo: mRNA profiles of 18 week fed Western diet wild type (WT) and Oct4-/- mice were generated by deep sequencing, four animals per group, using Illumina HiSeq 2000. In vitro: a smooth muscle cell wild type (WT) and Oct4-/- (KO) primary aortic cell line was generated and used. mRNA profiles were generated by deep sequencing, in triplicates, using Illumina HiSeq 2000, for the following groups: WT-normoxia-vehicle; WT-normoxia-POVPC; KO-normoxia-vehicle; KO-normoxia-POVP; WT-hypoxia-vehicle; WT-hypoxia-POVPC; KO-hypoxia-vehicle; and KO-hypoxia-POVPC.
2016-05-15 | E-GEOD-75044 | biostudies-arrayexpress
Project description:Group 1 -- WT or PRDM16-KO ex vivo murine MLL-AF9 cells, and PRDM16-KO AF9 cells overexpressing either f-PRDM16 or s-PRDM16. Group 2 -- WT or total PRDM16-KO murine HSCs isolated from adult BM. Group 3 -- WT or total PRDM16-KO murine HSCs isolated from fetal liver. Group 4 -- WT or f-PRDM16-KO murine HSCs (expressing s-PRDM16 only) isolated from fetal liver.
2018-06-08 | GSE112860 | GEO
Project description:All current smooth muscle cell (SMC) restricted Cre mice recombine floxed alleles in vascular and visceral SMCs. We generated a tamoxifen-inducible CreERT2 mouse, Itga8-CreERT2, and compared its activity to the widely used Myh11-CreERT2 mouse. Both CreERT2 mice showed similar activity in vascular SMCs; however, Itga8-CreERT2 displayed low activity in visceral SMC-containing tissues (e.g., intestine). Myh11-CreERT2 (but not Itga8-CreERT2) mice exhibited high levels of CreERT2 protein, tamoxifen-independent activity, and an altered transcriptome. Whereas Myh11-CreERT2-mediated knockout of Srf resulted in a lethal intestinal phenotype, loss of Srf with Itga8-CreERT2 (SrfItga8) revealed viable mice with attenuated vascular SMC contractile gene expression, but no evidence of intestinal pathology. Male and female SrfItga8 mice presented with vascular contractile incompetence; however, only male SrfItga8 mice showed systemic changes in blood pressure. These results establish the Itga8-CreERT2 mouse as an alternative to existing SMC Cre strains where gene loss may result in visceral myopathies that obfuscate accurate phenotyping in vascular SMCs.
2022-09-13 | GSE199244 | GEO