A5051653581- Atherosclerosis and Cardiovascular Diseases
- Angiogenesis and VEGF in Cancer
- Cardiac Fibrosis and Remodeling
- Cardiovascular Function and Risk Factors
- Single-cell and spatial transcriptomics
- Mitochondrial Function and Pathology
- Cell Adhesion Molecules Research
- Signaling Pathways in Disease
- FOXO transcription factor regulation
- Telomeres, Telomerase, and Senescence
- Calcium signaling and nucleotide metabolism
- Cancer-related molecular mechanisms research
- Nutrition, Genetics, and Disease
- Metabolomics and Mass Spectrometry Studies
- Adipose Tissue and Metabolism
- Cell death mechanisms and regulation
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Nutrition and Health in Aging
- Kruppel-like factors research
- PARP inhibition in cancer therapy
- Phagocytosis and Immune Regulation
- Medical and Biological Ozone Research
- Cardiac Valve Diseases and Treatments
- Circular RNAs in diseases
- Cardiac Health and Mental Health
University of Cambridge
2017-2025
Victor (Japan)
2025
Papworth Hospital
2023
Addenbrooke's Hospital
2017-2021
Chinese Academy of Medical Sciences & Peking Union Medical College
2018
University of Nottingham Malaysia Campus
2017
MRC Mitochondrial Biology Unit
2017
Wellcome Sanger Institute
2016
The Gurdon Institute
2016
University of Glasgow
2015
Rationale: Vascular smooth muscle cell (VSMC) accumulation is a hallmark of atherosclerosis and vascular injury. However, fundamental aspects proliferation the phenotypic changes within individual VSMCs, which underlie disease, remain unresolved. In particular, it not known whether all VSMCs proliferate display plasticity or cells can switch to multiple phenotypes. Objective: To assess in disease general characteristic feature subset cells. Methods Results: Using multicolor lineage labeling,...
Mitochondrial DNA (mtDNA) damage is present in murine and human atherosclerotic plaques. However, whether endogenous levels of mtDNA are sufficient to cause mitochondrial dysfunction decreasing improving respiration affects plaque burden or composition unclear. We examined plaques augmenting atherogenesis.Human showed marked dysfunction, manifested as reduced copy number oxygen consumption rate fibrous cap core regions. Vascular smooth muscle cells derived from impaired respiration, complex...
Summary Aging is the largest risk factor for cardiovascular disease, yet molecular mechanisms underlying vascular aging remain unclear. Mitochondrial DNA (mt ) damage linked to aging, but whether mt or mitochondrial dysfunction present and directly promotes unknown. Furthermore, mechanistic studies in mice are severely hampered by long study times lack of sensitive, repeatable reproducible parameters arterial at standardized early time points. We examined course multiple invasive noninvasive...
Abstract Aims Traditional markers of cell senescence including p16, Lamin B1, and senescence-associated beta galactosidase (SAβG) suggest very high frequencies senescent cells in atherosclerosis, while their removal via ‘senolysis’ has been reported to reduce atherogenesis. However, selective killing a variety different types can exacerbate atherosclerosis. We therefore examined the specificity vascular smooth muscle (VSMCs) effects genetic or pharmacological senolysis Methods results...
Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation contractile function protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression this condition failure. Consequently, new therapeutic targets urgently required achieve aim. Expression the Runx1 transcription factor increased adult cardiomyocytes after MI; however, functional role unknown.
Vascular smooth muscle cell (VSMC) apoptosis accelerates atherosclerosis and promotes breakdown of the extracellular matrix, but mechanistic links between these 2 processes are unknown. The forkhead protein FOXO3a (forkhead transcription factor O subfamily member 3a) is activated in human induces a range proapoptotic other transcriptional targets. We, therefore, determined mechanisms consequences activation arterial remodeling after injury.Expression conditional allele (FOXO3aA3ER) potently...
Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark multiple pathologies, including following neointimal formation after injury and atherosclerosis. However, human VSMCs in advanced atherosclerotic lesions show reduced cell proliferation, extensive persistent DNA damage, features premature senescence. Here, we report that stress-induced senescence (SIPS) stable expression telomeric repeat-binding factor 2 protein mutant (TRF2T188A) induce VSMCs, associated with damage. VSMC...
Abstract Aims Quiescent, differentiated adult vascular smooth muscle cells (VSMCs) can be induced to proliferate and switch phenotype. Such plasticity underlies blood vessel homeostasis contributes disease development. Oligoclonal VSMC contribution is a hallmark of end-stage disease. Here, we aim understand cellular mechanisms underpinning generation this oligoclonality. Methods results We investigate the dynamics clone formation using confocal microscopy single-cell transcriptomics in...
Aging leads to structural and functional deterioration of the heart, reducing its capacity withstand internal external stressors consequently increasing risk heart failure. Exercise is a potent modulator cardiovascular metabolic health, offering numerous physiological benefits that can persist throughout aging process. Studies suggest exercise decelerate age-related cardiac mitigate In this review, we discuss recent advances in our understanding exercise-mediated molecular cellular...
In the heart, a period of ischaemia followed by reperfusion evokes powerful cytosolic Ca(2+) oscillations that can cause lethal cell injury. These signals represent attractive cardioprotective targets, but underlying mechanisms genesis are ill-defined. Here, we investigated role second messenger nicotinic acid adenine dinucleotide phosphate (NAADP), which is known in several types to induce initiate from acidic stores such as lysosomes, likely via two-pore channels (TPCs, TPC1 and 2).An...
Vascular inflammation underlies cardiovascular disease. smooth muscle cells (VSMCs) upregulate selective genes, including MMPs (matrix metalloproteinases) and proinflammatory cytokines upon local inflammation, which directly contribute to vascular disease adverse clinical outcome. Identification of factors controlling VSMC responses is therefore considerable therapeutic importance. Here, we determine the role Histone H3 lysine 9 di-methylation (H3K9me2), a repressive epigenetic mark that...
Vascular smooth muscle cells (VSMCs) are the main structural cell of blood vessels, and VSMC apoptosis occurs in vascular disease, after injury, vessel remodeling during development. Although is viewed as silent, recent studies show that apoptotic can promote apoptosis-induced compensatory proliferation (AICP), (AIA), migration both local somatic infiltrating inflammatory cells. However, effects on adjacent VSMCs, their underlying signaling mechanisms unknown. We examined consequences...
Vascular aging is characterized by vessel stiffening, with increased deposition of extracellular matrix (ECM) proteins including collagens. Oxidative DNA damage occurs in vascular aging, but how it regulates ECM and stiffening unknown. We sought to determine the relationship between oxidative regulatory aging.
Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize diseases causing heart attack stroke. Here we elucidate molecular determinants governing VSMC by reconstructing gene regulatory networks from single-cell transcriptomics epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. compared network rewiring between injury-responsive nonresponsive VSMCs, which suggested shared transcription...
Abstract Aims Vascular smooth muscle cells (VSMCs) accumulate in atherosclerotic plaques and exhibit remarkable phenotypic plasticity, contributing to both plaque growth stability. The plaque-stabilising fibrous cap is rich VSMC-derived cells, yet the cellular transitions regulatory mechanisms governing formation remain unclear. We aimed delineate VSMC associated with this critical process. Methods Results Mapping of lineage-traced VSMCs during development revealed investment prior...
Abstract Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation are hallmarks of diseases causing heart attack stroke. To elucidate molecular determinants governing VSMC proliferation, we reconstructed gene regulatory networks from single transcriptomics epigenetic profiling. We find progressive activation enhancers at disease-relevant loci in VSMCs that don’t respond to injury proliferation-predisposed cells. Our analysis suggests while many transcription factors shared,...
ABSTRACT Rationale Vascular smooth muscle cell (VSMC) dysregulation is a hallmark of vascular disease, including atherosclerosis. In particular, the majority cells within atherosclerotic lesions are generated from pre-existing VSMCs and clonal nature has been documented for VSMC-derived in multiple disease models. However, mechanisms underlying generation oligoclonal phenotype proliferating unknown. Objective To understand cellular VSMC expansion disease. Methods Results Here we analyse...
<h3>Background</h3> Post-MI various cellular and extracellular matrix changes occur in the infarct, border zone (BZ) left ventricular (LV) regions of heart due to death cardiomyocytes. In a significant proportion patients with MI, these can lead adverse cardiac remodelling subsequent reduced myocardial function resulting failure (HF). The transcription factor Runx1, required for differentiation haematopoetic stem cells normally absent adult cardiomyoyctes, is switched on BZ Our objective...
Purpose: Myocardial ischaemia-reperfusion injury (IRI) is characterised by excessive intracellular levels of Ca2+ in cardiomyocytes which leads to mitochondrial pore opening and cell death. Nicotinic acid adenine dinucleotide phosphate (NAADP) a potent second messenger mobilises from lysosomes, turn can trigger release the sarcoplasmic reticulum (SR). Lethal oscillations occur during reoxygenation after simulated ischaemia. Ned-19 pharmacological inhibitor NAADP signalling we found...
<h3>Aims</h3> In atherosclerosis, vascular smooth muscle cells (VSMCs) dedifferentiate and acquire diverse phenotypes. These transdifferentiation pathways are poorly understood, including that underpinning generation of the VSMC-rich, plaque-stabilising fibrous cap. We aim to delineate VSMC in disease, with focus on cap formation. <h3>Methods Results</h3> Using single-cell RNA-sequencing VSMCs we computationally inferred five a common intermediate state (SCA1/Ly6a+, Vcam1+) but distinct...