Smooth muscle cells (SMCs) play a fundamental role in the development of atherosclerotic plaques. They ingest lipids in a similar way to monocyte-derived macrophages (MDMs) in the plaque. This can stimulate SMCs to undergo a phenotypic switch to a macrophage-like phenotype. We formulate an ordinary differential equation (ODE) model for the populations of SMCs, MDMs and smooth muscle cell-derived macrophages (SDMs) and the internalised lipid load in each population. We use this model to explore the effect on plaque fate of SMC phenotype switching. We find that when SMCs switch to a macrophage-like phenotype, there is an increase in the lipid quantity in the model plaque that is internalised inside cells. Additionally, removal of SMCs from the model plaque via phenotype switching reduces the number of SMCs in the fibrous cap, increases the lipid in the necrotic core, and increases plaque inflammation. These features are hallmarks of vulnerable plaques, whose rupture can cause heart attacks or strokes. When SDMs are highly proliferative or resistant to cell death, the model plaque becomes increasingly pathological. The model suggests that the switch of SMCs to a macrophage-like phenotype may drive the development of unstable and pathological plaques.

In a landmark study published in The New England Journal of Medicine,Laffin et al.1 present the first-in-human clinical evalua-tion of CTX310,an investigational in vivo CRISPR-Cas9 therapy engineered to induce permanent loss-of-function mutations in the hepatic ANGPTL3 gene,resulting in sustained lowering of atherogenic lipoproteins.This marks a major step toward durable,potentially lifelong lipid lowering through a single therapeutic intervention,1 potentially replacing years of ongoing lipid-lowering treatment for atherosclerotic cardiovascular disease(ASCVD)patients.

Many cells identified as macrophage-like in human and mouse atherosclerotic plaques are thought to be of vascular smooth muscle cell (VSMC) origin. We identified cholesterol-mediated down-regulation of TGFβ signaling in vitro in human (h)VSMCs by localization of TGFβ receptors in membrane lipid rafts, which was reversed by high-density lipoprotein (HDL)-mediated cholesterol efflux. This restored VSMC contractile marker (Acta2) and suppressed macrophage marker (CD68) expression by promoting TGFβ enhancement of Mir145 expression. In vivo, administration of ApoA1 (which forms HDL) to atherosclerotic mice also promoted VSMC Acta2 expression and reduced CD68 expression. Because macrophage-like VSMCs are thought to have adverse properties, our studies not only show mechanistically how cholesterol causes their transition, but also suggest that efflux-competent HDL particles may have a therapeutic role by restoring a more favorable phenotypic state of VSMCs in atherosclerotic plaques.

Dysfunctional endothelium with chronic inflammation represents an early stage in the development of atherosclerotic plaques. Nanomedicines capable of targeting activated endothelium and resolving inflammation have great potential for atherosclerosis treatment. In this work, we developed biomimetic platelet membrane‐coated layered double hydroxide nanoparticles (PM‐LDH) for the targeted delivery of anti‐inflammatory drug colchicine to the inflamed endothelial cells and showed improved therapeutic effects by using the colchicine‐loaded PM‐LDH. Inspired by the natural interactions between platelets and activated endothelium, platelet membrane‐coated nanoparticles exhibited markedly high affinity for inflamed endothelial cells while reducing immune clearance by macrophages. The enhanced anti‐inflammatory efficacy was demonstrated by reduced monocyte recruitment and attenuated reactive oxygen species production in inflamed endothelial cells. Overall, through the platelet membrane–endothelium interaction, the biomimetic colchicine‐loaded nanoparticles show strong potential as a targeted therapeutic strategy for atherosclerosis.

Anti-inflammatory colchicine therapy has emerged as a new era for atherosclerotic cardiovascular diseases. However, the therapeutic benefit of colchicine has not been clearly defined. Herein, we present a double coordination-driven approach to fabricate a stable metal-organic nano-assembly of colchicine (COL-TA-Zn) by uniting the tropolone ring of colchicine (COL), phenolic groups of tannic acid (TA), and Zn 2+ ions. This design leverages the antioxidant and anti-inflammatory properties of COL and TA to create a nanoscale platform capable of scavenging radicals and modulating inflammatory pathways. Through robust Zn 2+ coordination, the resulting COL-TA-Zn nanocomplexes exhibit enhanced stability under physiological conditions, ensuring efficient delivery and sustained bioactivity. In vitro assays confirm suppression of foam cell formation and multiple inflammatory mediators, suggesting significant potential for managing atherosclerosis by targeting both oxidative stress and inflammation. Intravenous administration of COL-TA-Zn in Apoe − / − mice significantly reduces atherosclerotic plaque area, MMP-9, TNF-α, and reactive oxygen species (ROS) levels, thereby illustrating its superior anti-atherosclerotic efficacy compared to COL alone. These findings highlight the promise of the dual coordination-driven nanoplatform in cardiovascular disease treatment.

Low-dose colchicine is the only anti-inflammatory drug approved for secondary prevention of coronary disease. The CLEAR-SYNGERY trial of colchicine in acute myocardial infarction challenges the results of previous colchicine trials; however, clinicians should be aware of how its design and the COVID-19 pandemic affected the trial outcome.

Atherosclerosis is a leading cause of cardiovascular morbidity and mortality worldwide, driven by complex interactions among various plaque cell types, including endothelial cells, macrophages, and smooth muscle cells. Traditional therapies targeting systemic risk factors such as cholesterol and blood pressure fail to directly address the underlying mechanisms governing plaque formation and progression. Recent advances in cell-specific therapies offer new avenues for targeting the cellular and molecular processes driving atherosclerosis. This Review explores innovative strategies including nanoparticles, viral vectors and CRISPR-Cas9 technology, which have the potential to modulate gene expression and behaviour within plaques cells to alleviate disease. By focusing on the specific roles of key cell types in atherosclerosis, these emerging therapies promise to provide more precise, effective, and personalised treatment options without inducing off-target effects. Moreover, insights gained from successful applications of these technologies in oncology are considered for potential repurposing in atherosclerosis-related disease. As these cell-specific approaches advance through preclinical and clinical development, they may significantly enhance our ability to treat atherosclerosis at its cellular roots, offering new hope for reducing the burden of cardiovascular disease.

Converging evidence indicates that extra-embryonic yolk sac is the source of both macrophages and endothelial cells in adult mouse tissues. Prevailing views are that these embryonically derived cells are maintained after birth by proliferative self-renewal in their differentiated states. Here we identify clonogenic endothelial-macrophage (EndoMac) progenitor cells in the adventitia of embryonic and postnatal mouse aorta, that are independent of Flt3-mediated bone marrow hematopoiesis and derive from an early embryonic CX3CR1+ and CSF1R+ source. These bipotent progenitors are proliferative and vasculogenic, contributing to adventitial neovascularization and formation of perfused blood vessels after transfer into ischemic tissue. We establish a regulatory role for angiotensin II, which enhances their clonogenic and differentiation properties and rapidly stimulates their proliferative expansion in vivo. Our findings demonstrate that embryonically derived EndoMac progenitors participate in local vasculogenic responses in the aortic wall by contributing to the expansion of endothelial cells and macrophages postnatally. The extraembryonic yolk sac is a major location for developmental hematopoiesis, but it is unclear whether non-bone marrow sources contribute during adulthood. Here they show that embryonically derived endothelial-macrophage progenitor cells located in the aorta are a bipotent source of macrophage and endothelial cells later in life.

Vascular smooth muscle cells, endothelial cells and macrophages undergo phenotypic conversions throughout atherosclerosis progression, both as a consequence of chronic inflammation and as subsequent drivers of it. The inflammatory hypothesis of atherosclerosis has been catapulted to the forefront of cardiovascular research as clinical trials have shown that anti-inflammatory therapy reduces adverse cardiovascular events. However, no current therapies have been specifically designed to target the phenotype of plaque cells. Fate mapping has revealed that plaque cells convert to detrimental and beneficial cell phenotypes during atherosclerosis, with cumulative evidence highlighting that vascular cell plasticity is intimately linked with plaque inflammation, ultimately impacting lesion stability. Here we review vascular cell plasticity during atherosclerosis in the context of the chronic inflammatory plaque microenvironment. We highlight the need to better understand how plaque cells behave during therapeutic intervention. We then propose modulating plaque cell phenotype as an unexplored therapeutic paradigm in the clinical setting.

Smooth muscle cells, endothelial cells and macrophages display remarkable heterogeneity within the healthy vasculature and under pathological conditions. During development, these cells arise from numerous embryological origins, which confound with different microenvironments to generate postnatal vascular cell diversity. In the atherosclerotic plaque milieu, all these cell types exhibit astonishing plasticity, generating a variety of plaque burdening or plaque stabilizing phenotypes. And yet how developmental origin influences intraplaque cell plasticity remains largely unexplored despite evidence suggesting this may be the case. Uncovering the diversity and plasticity of vascular cells is being revolutionized by unbiased single cell whole transcriptome analysis techniques that will likely continue to pave the way for therapeutic research. Cellular plasticity is only just emerging as a target for future therapeutics, and uncovering how intraplaque plasticity differs across vascular beds may provide key insights into why different plaques behave differently and may confer different risks of subsequent cardiovascular events.

Atherosclerosis, a chronic cardiovascular disease caused by plaque development in arteries, remains a leading cause of morbidity and mortality. Atherosclerotic plaques are characterized by the expression and regulation of key molecules such as cell surface receptors, cytokines, and signaling pathway proteins, potentially facilitating precise diagnosis and treatment on a molecular level by specifically targeting the characteristic molecules. In this review, we highlight the recent progress in the past five years on developing molecularly targeted nanomedicine for imaging detection and treatment of atherosclerosis with the use of inorganic nanoparticles. Through targeted delivery of imaging contrast nanoparticles to specific molecules in atherogenesis, atherosclerotic plaque development at different stages could be identified and monitored via various molecular imaging modalities. We also review molecularly targeted therapeutic approaches that target and regulate molecules associated with lipid regulation, inflammation, and apoptosis. The review is concluded with discussion on current challenges and future development of nanomedicine for atherosclerotic diagnosis and treatment.

Introduction: We conducted a systematic review and meta-analysis to review the relationship between midlife dyslipidemia and lifetime incident dementia. Methods: The databases Medline, Embase, Scopus, Web of Science, and Cochrane were searched from inception to February 20, 2022. Longitudinal studies examining the relationship between midlife lipid levels on dementia, dementia subtypes, and/or cognitive impairment were pooled using inverse-variance weighted random-effects meta-analysis. Results: Seventeen studies (1.2 million participants) were included. Midlife hypercholesterolemia was associated with increased incidence of mild cognitive impairment (effect size [ES] = 2.01; 95% confidence interval [CI] 1.19 to 2.84; I-2 = 0.0%) and all-cause dementia (ES = 1.14; 95% CI: 1.07 to 1.21; I-2 = 0.0%). Each 1 mmol/L increase in low-density lipoprotein was associated with an 8% increase (ES = 1.08, 95% CI: 1.03 to 1.14; I-2 = 0.3%) in incidence of all-cause dementia. Discussion: Midlife dyslipidemia is associated with an increased risk of cognitive impairment in later life.

PURPOSE:Despite an increase in treatment options, and substantial reductions in cardiovascular mortality over the past half-century, atherosclerosis remains the most prevalent cause of premature mortality worldwide. The development of innovative new therapies is crucial to further minimize atherosclerosis-related deaths. The diverse array of cell phenotypes derived from vascular smooth muscle cells (SMCs) and macrophages within atherosclerotic plaques are increasingly becoming recognized for their beneficial and detrimental roles in plaque stability and disease burden. This review explores how contemporary transcriptomics and fate-mapping studies have revealed vascular cell plasticity as a relatively unexplored target for therapeutic intervention.METHODS:Recent literature for this narrative review was obtained by searching electronic databases (ie, Google Scholar, PubMed). Additional studies were sourced from reference lists and the authors' personal databases.FINDINGS:The lipid-rich and inflammatory plaque milieu induces SMC phenotypic switching to both beneficial and detrimental phenotypes. Likewise, macrophage heterogeneity increases with disease burden to a variety of pro-inflammatory and anti-inflammatory activation states. These vascular cell phenotypes are determinants of plaque structure stability, and it is therefore highly likely that they influence clinical outcomes. Development of clinical treatments targeting deleterious phenotypes or promoting pro-healing phenotypes remains in its infancy. However, existing treatments (statins) have shown beneficial effects toward macrophage polarization, providing a rationale for more targeted approaches. In contrast, beneficial SMC phenotypic modulation with these pharmacologic agents has yet to be achieved. The range of modulated vascular cell phenotypes provides a multitude of novel targets and the potential to reduce future adverse events.IMPLICATIONS:Vascular cell phenotypic heterogeneity must continue to be explored to lower cardiovascular events in the future. The rapidly increasing weight of evidence surrounding the role of SMC plasticity and macrophage polarity in plaque vulnerability provides a strong foundation upon which development of new therapeutics must follow. This approach may prove to be crucial in reducing cardiovascular events and improving patient benefit in the future.

Atherosclerosis is a chronic inflammatory disease which is driven in part by the aberrant trans -differentiation of vascular smooth muscle cells (SMCs). No therapeutic drug has been shown to reverse detrimental SMC-derived cell phenotypes into protective phenotypes, a hypothesized enabler of plaque regression and improved patient outcome. Herein, we describe a novel function of colchicine in the beneficial modulation of SMC-derived cell phenotype, independent of its conventional anti-inflammatory effects. Using SMC fate mapping in an advanced atherosclerotic lesion model, colchicine induced plaque regression by converting pathogenic SMC-derived macrophage-like and osteoblast-like cells into protective myofibroblast-like cells which thickened, and thereby stabilized, the fibrous cap. This was dependent on Notch3 signaling in SMC-derived plaque cells. These findings may help explain the success of colchicine in clinical trials relative to other anti-inflammatory drugs. Thus, we demonstrate the potential of regulating SMC phenotype in advanced plaque regression through Notch3 signaling, in addition to the canonical anti-inflammatory actions of drugs to treat atherosclerosis.

Clonal expansion refers to the proliferation and selection of advantageous "clones" that are better suited for survival in a Darwinian manner. In recent years, we have greatly enhanced our understanding of cell clonality in the cardiovascular context. However, our knowledge of the underlying mechanisms behind this clonal selection is still severely limited. There is a transpiring pattern of clonal expansion of smooth muscle cells and endothelial cells — and, in some cases, macrophages — in numerous cardiovascular diseases irrespective of their differing microenvironments. These findings indirectly suggest the possible existence of stem-like vascular cells which are primed to respond during disease. Subsequent clones may undergo further phenotypic changes to adopt either protective or detrimental roles. By investigating these clone-forming vascular cells, we may be able to harness this inherent clonal nature for future therapeutic intervention. This review comprehensively discusses what is currently known about clonal expansion across the cardiovascular field. Comparisons of the clonal nature of vascular cells in atherosclerosis (including clonal hematopoiesis of indeterminate potential), pulmonary hypertension, aneurysm, blood vessel injury, ischemia- and tumor-induced angiogenesis, and cerebral cavernous malformations are evaluated. Finally, we discuss the potential clinical implications of these findings and propose that proper understanding and specific targeting of these clonal cells may provide unique therapeutic options for the treatment of these cardiovascular conditions.

Clonal expansion is a process that can drive pathogenesis in human diseases, with atherosclerosis being a prominent example. Despite advances in understanding the etiology of atherosclerosis, clonality studies of vascular cells remain in an early stage. Recently, several paradigm-shifting preclinical studies have identified clonal expansion of progenitor cells in the vasculature in response to atherosclerosis. This review provides an overview of cell clonality in atherosclerotic progression, focusing particularly on smooth muscle cells and macrophages. We discuss key findings from the latest research that give insight into the mechanisms by which clonal expansion of vascular cells contributes to disease pathology. The further probing of these mechanisms will provide innovative directions for future progress in the understanding and therapy of atherosclerosis and its associated cardiovascular diseases.

Obstructive arterial diseases, including supravalvular aortic stenosis (SVAS), atherosclerosis, and restenosis, share 2 important features: an abnormal or disrupted elastic lamellae structure and excessive smooth muscle cells (SMCs). However, the relationship between these pathological features is poorly delineated. SVAS is caused by heterozygous loss-of-function, hypomorphic, or deletion mutations in the elastin gene (ELN), and SVAS patients and elastin-mutant mice display increased arterial wall cellularity and luminal obstructions. Pharmacological treatments for SVAS are lacking, as the underlying pathobiology is inadequately defined. Herein, using human aortic vascular cells, mouse models, and aortic samples and SMCs derived from induced pluripotent stem cells of ELN-deficient patients, we demonstrated that elastin insufficiency induced epigenetic changes, upregulating the NOTCH pathway in SMCs. Specifically, reduced elastin increased levels of γ-secretase, activated NOTCH3 intracellular domain, and downstream genes. Notch3 deletion or pharmacological inhibition of γ-secretase attenuated aortic hypermuscularization and stenosis in Eln–/– mutants. Eln–/– mice expressed higher levels of NOTCH ligand JAGGED1 (JAG1) in aortic SMCs and endothelial cells (ECs). Finally, Jag1 deletion in SMCs, but not ECs, mitigated the hypermuscular and stenotic phenotype in the aorta of Eln–/– mice. Our findings reveal that NOTCH3 pathway upregulation induced pathological aortic SMC accumulation during elastin insufficiency and provide potential therapeutic targets for SVAS.

Colchicine, an inexpensive immunomodulatory drug used traditionally to treat gout and familial Mediterranean fever, is rapidly accumulating basic and clinical evidence for a therapeutic role in atherosclerotic cardiovascular disease. Its athero-protective properties are thought to be mainly related to its effect on tubulin polymerisation, enabling a broad range of effect on multiple atherosclerotic plaque cell types and cellular processes, including cell division, cell migration as well as pro-inflammatory cytokine and chemokine secretion. These properties indicate the potential to favourably affect all stages of atherosclerotic plaque development including formation, progression, destabilisation, and plaque rupture. This review focusses on the pharmacology of colchicine, the mechanisms by which it modulates atherosclerosis pathobiology, and summarises the current clinical evidence for its use along with the upcoming clinical trial landscape. Given the current lack of primary immunomodulatory drugs in the treatment of atherosclerosis, colchicine is a promising candidate to fill this therapeutic gap.