Epigenetic regulation of vascular smooth muscle cell phenotypes in atherosclerosis.

Vascular smooth muscle cells (VSMCs) in adult arteries maintain substantial phenotypic plasticity, which allows for the reversible cell state changes that enable vascular remodelling and homeostasis. In atherosclerosis, VSMCs dedifferentiate in response to lipid accumulation and inflammation, resulting in loss of their characteristic contractile state. Recent studies showed that individual, pre-existing VSMCs expand clonally and can acquire many different phenotypes in atherosclerotic lesions.

Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease.

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.

Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease.

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.

Risk of Depression after Venous Thromboembolism in Patients with Hematological Cancer: A Population-Based Cohort Study.

Background:  Venous thromboembolism (VTE) may complicate the clinical course of cancer patients and add to their psychological burden.

Objectives:  We aimed to investigate the association between VTE and risk of subsequent depression in patients with hematological cancer.

Patients And Methods:  We conducted a population-based cohort study using Danish national health registries.

Selenoprotein deficiency disorder predisposes to aortic aneurysm formation.

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.

Designing Ecological Auditory Feedback on Lower Limb Kinematics for Hemiparetic Gait Training.

Auditory feedback has earlier been explored as a tool to enhance patient awareness of gait kinematics during rehabilitation. In this study, we devised and tested a novel set of concurrent feedback paradigms on swing phase kinematics in hemiparetic gait training. We adopted a user-centered design approach, where kinematic data recorded from 15 hemiparetic patients was used to design three feedback algorithms (wading sounds, abstract, musical) based on filtered gyroscopic data from four inexpensive wireless inertial units.

Somatostatin Receptor PET/MR Imaging of Inflammation in Patients With Large Vessel Vasculitis and Atherosclerosis.

Background: Assessing inflammatory disease activity in large vessel vasculitis (LVV) can be challenging by conventional measures.

Objectives: We aimed to investigate somatostatin receptor 2 (SST) as a novel inflammation-specific molecular imaging target in LVV.

Methods: In a prospective, observational cohort study, in vivo arterial SST expression was assessed by positron emission tomography/magnetic resonance imaging (PET/MRI) using Ga-DOTATATE and F-FET-βAG-TOCA.

Venous thromboembolism and risk of depression: a population-based cohort study.

Background: The psychologic consequences of acute venous thromboembolism (VTE) have not been investigated in depth.

Objectives: We aimed to examine the association between VTE and the risk of subsequent depression.

Methods: Using Danish nationwide registries, we established a population-based cohort of 64 596 individuals with incident VTE during 1996 to 2016 and a comparison cohort (n = 322 999) selected randomly from the general population and individually matched by birth year, sex, and calendar year of VTE.

Translational opportunities of single-cell biology in atherosclerosis.

The advent of single-cell biology opens a new chapter for understanding human biological processes and for diagnosing, monitoring, and treating disease. This revolution now reaches the field of cardiovascular disease (CVD). New technologies to interrogate CVD samples at single-cell resolution are allowing the identification of novel cell communities that are important in shaping disease development and direct towards new therapeutic strategies.

JAG1-NOTCH4 mechanosensing drives atherosclerosis.

Endothelial cell (EC) sensing of disturbed blood flow triggers atherosclerosis, a disease of arteries that causes heart attack and stroke, through poorly defined mechanisms. The Notch pathway plays a central role in blood vessel growth and homeostasis, but its potential role in sensing of disturbed flow has not been previously studied. Here, we show using porcine and murine arteries and cultured human coronary artery EC that disturbed flow activates the JAG1-NOTCH4 signaling pathway.

Cellular mechanisms of oligoclonal vascular smooth muscle cell expansion in cardiovascular disease.

Aims: Quiescent, differentiated adult vascular smooth muscle cells (VSMCs) can be induced to proliferate and switch phenotype. Such plasticity underlies blood vessel homeostasis and contributes to vascular disease development. Oligoclonal VSMC contribution is a hallmark of end-stage vascular disease.

The Interaction Between Venous Thromboembolism and Socioeconomic Status on the Risk of Disability Pension.

Background: Venous thromboembolism (VTE) is associated with increased risk of disability pension. How socioeconomic status (SES) impacts the risk of disability pension after a VTE is unknown. The aim of this nationwide population based cohort study to investigate the interaction between SES and incident VTE on the risk of subsequent disability pension.

Socioeconomic status and risk of incident venous thromboembolism.

Background: Although venous thromboembolism (VTE) is a leading cause of morbidity and mortality, and socioeconomic status (SES) affects human health and health behavior, few studies have examined the association between SES and VTE.

Objectives: We aimed to investigate the association between SES, assessed individually and in a composite score by levels of education, income, and employment status, and incident VTE.

Methods: We used Danish national registries to identify 51 350 persons aged 25-65 years with incident VTE during 1995-2016.

Mechanisms of vascular smooth muscle cell investment and phenotypic diversification in vascular diseases.

In contrast with the heart, the adult mammalian vasculature retains significant remodelling capacity, dysregulation of which is implicated in disease development. In particular, vascular smooth muscle cells (VSMCs) play major roles in the pathological vascular remodelling characteristic of atherosclerosis, restenosis, aneurysm and pulmonary arterial hypertension. Clonal lineage tracing revealed that the VSMC-contribution to disease results from the hyperproliferation of few pre-existing medial cells and suggested that VSMC-derived cells from the same clone can adopt diverse phenotypes.

Risk of a permanent work-related disability pension after incident venous thromboembolism in Denmark: A population-based cohort study.

Background: Long-term complications of venous thromboembolism (VTE) hamper physical function and impair quality of life; still, it remains unclear whether VTE is associated with risk of permanent work-related disability. We aimed to assess the association between VTE and the risk of receiving a permanent work-related disability pension and to assess whether this association was explained by comorbidities such as cancer and arterial cardiovascular disease.

Methods And Findings: A Danish nationwide population-based cohort study consisting of 43,769 individuals aged 25 to 66 years with incident VTE during 1995 to 2016 and 218,845 birth year-, sex-, and calendar year-matched individuals from the general population, among whom 45.

APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans.

Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide. The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs) and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall. A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs, but the physiology of this interaction is largely unknown.

Efficacy and limitations of senolysis in atherosclerosis.

Aims: Traditional markers of cell senescence including p16, Lamin B1, and senescence-associated beta galactosidase (SAβG) suggest very high frequencies of senescent cells in atherosclerosis, while their removal via 'senolysis' has been reported to reduce atherogenesis. However, selective killing of a variety of different cell types can exacerbate atherosclerosis. We therefore examined the specificity of senescence markers in vascular smooth muscle cells (VSMCs) and the effects of genetic or pharmacological senolysis in atherosclerosis.

Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury.

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 (TRF2) induce senescence of human VSMCs, associated with persistent telomeric DNA damage.

DNA glycosylase Neil3 regulates vascular smooth muscle cell biology during atherosclerosis development.

Background And Aims: Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability.

Epigenetic Regulation of Vascular Smooth Muscle Cells by Histone H3 Lysine 9 Dimethylation Attenuates Target Gene-Induction by Inflammatory Signaling.

Objective: Vascular inflammation underlies cardiovascular disease. Vascular smooth muscle cells (VSMCs) upregulate selective genes, including MMPs (matrix metalloproteinases) and proinflammatory cytokines upon local inflammation, which directly contribute to vascular disease and adverse clinical outcome. Identification of factors controlling VSMC responses to inflammation is therefore of considerable therapeutic importance.

The role of smooth muscle cells in plaque stability: Therapeutic targeting potential.

Events responsible for cardiovascular mortality and morbidity are predominantly caused by rupture of "vulnerable" atherosclerotic lesions. Vascular smooth muscle cells (VSMCs) play a key role in atherogenesis and have historically been considered beneficial for plaque stability. VSMCs constitute the main cellular component of the protective fibrous cap within lesions and are responsible for synthesising strength-giving extracellular matrix components.