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Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific developmental history and show heterogeneous expression of vascular disease-associated genes involved in inflammation, adhesion and migration. We detect a rare population of VSMC-lineage cells that express the multipotent progenitor marker Sca1, progressively downregulate contractile VSMC genes and upregulate genes associated with VSMC response to inflammation and growth factors. We find that Sca1 upregulation is a hallmark of VSMCs undergoing phenotypic switching in vitro and in vivo, and reveal an equivalent population of Sca1-positive VSMC-lineage cells in atherosclerotic plaques. Together, our analyses identify disease-relevant transcriptional signatures in VSMC-lineage cells in healthy blood vessels, with implications for disease susceptibility, diagnosis and prevention. Vascular smooth muscle cell (VSMC) accumulation is associated with cardiovascular disease. Here, the authors combine single-cell RNA sequencing with lineage labelling to profile VSMC heterogeneity in healthy mice. They show that upregulation of Sca1 in a rare VSMC subpopulation marks a cell phenotype that is prevalent in disease.

Epigenetic genome modifications are thought to be important for specifying the lineage and developmental stage of cells within a multicellular organism. Here, we show that the epigenetic profile of pluripotent embryonic stem cells (ES) is distinct from that of embryonic carcinoma cells, haematopoietic stem cells (HSC) and their differentiated progeny. Silent, lineage-specific genes replicated earlier in pluripotent cells than in tissue-specific stem cells or differentiated cells and had unexpectedly high levels of acetylated H3K9 and methylated H3K4. Unusually, in ES cells these markers of open chromatin were also combined with H3K27 trimethylation at some non-expressed genes. Thus, pluripotency of ES cells is characterized by a specific epigenetic profile where lineage-specific genes may be accessible but, if so, carry repressive H3K27 trimethylation modifications. H3K27 methylation is functionally important for preventing expression of these genes in ES cells as premature expression occurs in embryonic ectoderm development ( Eed )-deficient ES cells. Our data suggest that lineage-specific genes are primed for expression in ES cells but are held in check by opposing chromatin modifications.

Fisher and colleagues find that Jarid2 is a subunit of PRC2 (Polycomb Repressor Complex 2) that recruits PRC1 complex and Ser 5-phosphorylated RNA Polymerase II to developmental regulators in embryonic stem (ES) cells. Jarid2-deficient ES cells do not efficiently differentiate to mesoderm or neural lineages in vitro . Polycomb Repressor Complexes (PRCs) are important regulators of embryogenesis. In embryonic stem (ES) cells many genes that regulate subsequent stages in development are enriched at their promoters for PRC1, PRC2 and Ser 5-phosphorylated RNA Polymerase II (RNAP), and contain domains of 'bivalent' chromatin (enriched for H3K4me3; histone H3 di- or trimethylated at Lys 4 and H3K27me3; histone H3 trimethylated at Lys 27). Loss of individual PRC components in ES cells can lead to gene de-repression and to unscheduled differentiation. Here we show that Jarid2 is a novel subunit of PRC2 that is required for the co-recruitment of PRC1 and RNAP to genes that regulate development in ES cells. Jarid2-deficient ES cells showed reduced H3K4me2/me3 and H3K27me3 marking and PRC1/PRC2 recruitment, and did not efficiently establish Ser 5-phosporylated RNAP at target genes. ES cells lacking Jarid2, in contrast to previously characterized PRC1 and PRC2 mutants, did not inappropriately express PRC2 target genes. Instead, they show a severely compromised capacity for successful differentiation towards neural or mesodermal fates and failed to correctly initiate lineage-specific gene expression in vitro . Collectively, these data indicate that transcriptional priming of bivalent genes in pluripotent ES cells is Jarid2-dependent, and suggests that priming is critical for subsequent multi-lineage differentiation.

Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 ( SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient’s cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration. Aortic aneurysms have a heritable basis. Here, the authors report that a selenoprotein deficiency disorder due to mutations in SECISBP2, causes oxidative stress-mediated aortic cell death, predisposing to thoracic aortic aneurysm formation.

Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide 1 . The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs) 2 and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall 2 . A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs 3 , but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis. The heparan sulfate proteoglycan-binding cytokine APRIL has a protective role against atherosclerotic disease.

Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages of an atherosclerotic plaque. According to the ‘response to injury’ and ‘vulnerable plaque’ hypotheses, contractile VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that generate extracellular matrix to form the fibrous cap and hence stabilize plaques. However, lineage-tracing studies have highlighted flaws in the interpretation of former studies, revealing that these studies had underestimated both the content and functions of VSMCs in plaques and have thus challenged our view on the role of VSMCs in atherosclerosis. VSMCs are more plastic than previously recognized and can adopt alternative phenotypes, including phenotypes resembling foam cells, macrophages, mesenchymal stem cells and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this Review, we present the evidence for VSMC plasticity and summarize the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatiotemporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.

The original version of this Article contained errors in the author affiliations.Martin R. Bennett was incorrectly associated with Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, Phoebe Oldach was incorrectly associated with Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.This has now been corrected in the HTML version of the Article. The PDF version of the Article was correct at the time of publication

Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize vascular diseases causing heart attack and stroke. Here we elucidate molecular determinants governing VSMC proliferation by reconstructing gene regulatory networks from single-cell transcriptomics and epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. We compared gene regulatory network rewiring between injury-responsive and nonresponsive VSMCs, which suggested shared transcription factors but differing target loci between VSMC states. Through in silico perturbation analysis, we identified and prioritized previously unrecognized regulators of proliferation, including RUNX1 and TIMP1. Moreover, we showed that the pioneer transcription factor RUNX1 increased VSMC responsiveness and that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signaling. Both RUNX1 and the TIMP1–CD74 axis were expressed in human VSMCs, showing low levels in normal arteries and increased expression in disease, suggesting clinical relevance and potential as vascular disease targets.

Atherosclerotic lesions show significant mitochondrial dysfunction but the underlying mechanisms and consequences remain unknown. Cardiolipin is a phospholipid found exclusively in the mitochondrial inner membrane, the site of oxidative phosphorylation. Tafazzin is a trans-acylase that acylates immature monolysocardiolipin to mature cardiolipin. Tafazzin mutations can result in Barth’s Syndrome, which is characterised by dilated cardiomyopathy, skeletal myopathy and impaired growth. However, a role for tafazzin in atherosclerosis development has not been previously identified. Here we show that tafazzin expression is decreased in atherosclerotic lesions and specifically in plaque vascular smooth muscle cells (VSMCs). MicroRNA 125a-5p expression is increased in plaques, downregulates tafazzin expression and is induced by oxidised low-density lipoprotein in a NFκB-dependent manner. Silencing tafazzin or overexpression of mutant tafazzin decreases VSMC cardiolipin content and mitochondrial respiration, and promotes apoptosis and atherosclerosis. In contrast tafazzin overexpression increases respiration, protects against apoptosis and increases features of plaque stability. Tafazzin therefore has important effects on VSMC mitochondrial function and atherosclerosis, and is a potential therapeutic target in atherosclerotic disease. Atherosclerosis is the leading cause of death worldwide. Here, the authors show that defective vascular smooth muscle cell tafazzin promotes mitochondrial dysfunction and atherosclerosis, highlighting tafazzin as a potential therapeutic target.

Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of multiple vascular pathologies, including following neointimal formation after injury and atherosclerosis. However, human VSMCs in advanced atherosclerotic lesions show reduced cell proliferation, extensive and persistent DNA damage, and features of premature cell senescence. Here, we report that stress-induced premature senescence (SIPS) and stable expression of a telomeric repeat-binding factor 2 protein mutant (TRF2T188A) induce senescence of human VSMCs, associated with persistent telomeric DNA damage. VSMC senescence is associated with formation of micronuclei, activation of cGAS-STING cytoplasmic sensing, and induction of multiple pro-inflammatory cytokines. VSMC-specific TRF2T188A expression in a multicolor clonal VSMC-tracking mouse model shows no change in VSMC clonal patches after injury, but an increase in neointima formation, outward remodeling, senescence and immune/inflammatory cell infiltration or retention. We suggest that persistent telomere damage in VSMCs inducing cell senescence has a major role in driving persistent inflammation in vascular disease.Anna Uryga and Mandy Grootaert et al. combine cell culture and animal models to examine how senescence of human vascular smooth muscle cells (VSMCs) and persistent telomere damage drive inflammation. Their results suggest that telomere injury can be the primary cause of premature senescence in VSMCs, and that DNA damage can be a major cause of persistent inflammation in vascular disease.