Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

Background: Type 2 diabetes is associated with accelerated vascular complications such as hypertension and atherosclerosis. Phenotypic switching of vascular smooth muscle cells (SMCs), a major driver of these complications, is enhanced in diabetes. Despite adequate glycemic control, SMC dysfunction can persist due to metabolic memory of prior hyperglycemia. However, the mechanisms are unclear. Here, leveraging single-cell multiomics, we examined the effect of glucose normalization on transcriptomic and epigenomic changes associated with SMC phenotypic transition in type 2 diabetes mice.

Methods: Type 2 diabetes db/db mice were treated with the antidiabetic drug dapagliflozin (DAPA) or vehicle and nondiabetic control db/+ mice with vehicle for 6 weeks. Dissected aortas were subjected to single-cell RNA sequencing, single-cell assay for transposase-accessible chromatin with sequencing, and spatial transcriptomics (Xenium) to determine single-cell changes in gene expression and chromatin accessibility.

Results: DAPA conferred effective glycemic control in db/db mice, with significant reductions in blood glucose and hemoglobinA1c. scRNA and single-cell assay for transposase-accessible chromatin with sequencing analysis of aortas identified SMC, fibroblasts, endothelial, and immune cells. SMCs were further clustered into 9 subtypes, including contractile and fibromyocyte-like cells. Interestingly, SMC contractile phenotype-associated pathways decreased in diabetes and remained decreased despite DAPA treatment. Fibrosis and inflammation-associated pathways in SMC and fibroblasts, and dysfunction markers in endothelial cells, increased in diabetes and were partly reversed by DAPA. Pseudotime trajectory analysis of SMC revealed increased activities of fibromyocyte-enriched TFs (transcription factors) during the contractile to fibromyocyte transition. Pairwise analysis for differentially accessible regions revealed diabetes-associated differentially accessible regions, enrichment of TF motifs, and related disease-associated biological processes. However, no differentially accessible regions were identified between db/db and db/dbDAPA groups. Spatial transcriptomics mapped aortic cell types within intact aortas and validated sc-seq data.

Conclusions: Type 2 diabetes induces gene expression and chromatin accessibility changes associated with profound SMC phenotypic switching. These changes are not efficiently reversed by a widely used antidiabetic drug, DAPA, underscoring the need for more effective therapies targeting hyperglycemic memory.

Achieving a mature arteriovenous fistula (AVF) for hemodialysis remains a significant challenge, even for the most experienced vascular surgeons. Despite decades of research, ≈40% of new AVFs require salvage interventions or can never be used for dialysis. All clinical trials aimed at improving early AVF maturation have failed. This underscores the limitations of the existing biological model, which continues to frame stenosis through a reductionist lens centered on intimal hyperplasia, despite emerging evidence that this explanation is insufficient. This review seeks to redefine the biological framework of early AVF failure by adopting a human-centered perspective. In contrast to the prevailing paradigm, primarily built upon experimental data, our model is centered on human observational research and clinical trials. We then incorporate experimental data to provide mechanistic insights and contextualize or contrast the differences between human and animal biology. We unravel the biology of AVF maturation through 2 tightly connected phases: the acute biomechanical response, encompassing immediate structural and hemodynamic changes after AVF creation, and the subsequent vascular healing and remodeling processes that determine the long-term adaptation of the vein to supraphysiological circulation. By integrating these phases into a cohesive framework, this review advances a more comprehensive model of early AVF maturation failure, highlights therapeutic opportunities, and underscores that meaningful innovation in AVF biology remains both necessary and achievable.

Sarcoidosis is a chronic inflammatory disease of unknown cause that can affect the heart and blood vessels, causing cardiomyopathy, pulmonary hypertension, and vasculitis. The pathological hallmark of sarcoidosis is the formation of noncaseating granulomas consisting of monocytes and dendritic cells, macrophages, multinucleated giant cells, and T cells. Sarcoidosis has features of autoimmune disease, and many candidate self-epitopes have been identified, but experimental validation is lacking. There is a strong hereditary component associated with the human leukocyte antigen region on chromosome 6. Symptoms of the disease may be subtle and often go unrecognized by patients and practitioners. Catastrophic events, including sudden cardiac death caused by lethal arrhythmias, can be the initial manifestation of the disease. Diagnosis is challenging and limited by the lack of sensitive and specific diagnostic tools, which also hampers monitoring of disease activity. Here, we discuss the cardiovascular manifestations and underlying immunobiology of sarcoidosis. We also review current diagnostic and treatment approaches for cardiac sarcoidosis, as well as the challenges faced by patients and clinicians and opportunities for future research.

Background: Medial arterial calcification is a common lesion associated with aging, chronic kidney disease, and diabetes that can lead to poor outcomes. Because the calcification is extensive when first apparent clinically or even radiologically, optimal therapy should target reversal in addition to prevention. However, studies to date suggest that medial calcification is irreversible under physiological conditions. This lack of reversal was investigated further by implanting calcified human arteries or hydroxyapatite subcutaneously into mice, or culturing them with murine osteoclasts in vitro.

Methods: Calcified human tibial arteries, obtained from amputations and previously frozen, were implanted subcutaneously in the dorsum of mice. Mineral content was measured by microcomputed tomography before and after implantation and compared with the calcium content of implanted pure hydroxyapatite or murine bone particles, along with histology. Calcified arteries were also incubated in vitro with osteoclasts generated by treating murine macrophages with receptor activator of NF-κB (nuclear factor kappa B).

Results: There was no decrease in mineral content of implanted arteries over 6 weeks and only minimal loss of calcium in devitalized bone particles, compared with almost complete resorption of hydroxyapatite. No resorption of hydroxyapatite occurred when implanted within a cell-impermeable diffusion chamber. Multinucleated giant cells, negative for osteoclast markers, were numerous among implanted hydroxyapatite, but rare in implanted arteries and bone. There was no histological evidence of resorption in calcified arteries incubated with osteoclasts.

Conclusions: Hydroxyapatite is readily reabsorbed in vivo by a cell-mediated process not involving osteoclasts. The lack of resorption of medial arterial calcifications, even in the presence of osteoclasts, indicates that calcifications have properties that prevent cell-mediated resorption. Further studies are needed to identify these properties and develop strategies to overcome this.

Efferocytosis, the process by which phagocytes clear apoptotic cells, is essential for tissue homeostasis, inflammation resolution, and repair. Once considered a passive waste-disposal process, efferocytosis is now recognized as a dynamic, immunometabolic program that integrates apoptotic cell clearance with metabolic reprogramming and inflammation resolution. In cardiovascular contexts, efficient efferocytosis limits necrosis, enhances the deposition of wound healing matrix proteins, and promotes tissue healing, whereas impaired clearance drives chronic inflammation and maladaptive tissue remodeling. We review the molecular mechanisms governing efferocytosis, including the interplay of find-me, eat-me, and don't-eat-me signals with receptor-mediated cytoskeletal remodeling and lysosomal degradation. We highlight how efferocytosis drives lipid efflux, fatty acid oxidation, amino acid catabolism, and nucleotide recycling, processes that sustain continual efferocytosis and resolution programming. Defects in these pathways, amplified by proteolytic cleavage of apoptotic cell receptors, dysregulated metabolism, and inflammatory mediators, underlie impaired efferocytosis in atherosclerosis, myocardial infarction, vascular aging, and metabolic diseases. Finally, we discuss emerging concepts, including nonprofessional phagocyte contributions, crosstalk with adaptive immunity, and therapeutic strategies to enhance efferocytosis or preserve receptor integrity. Collectively, these insights redefine efferocytosis as more than a cleanup mechanism, positioning it as a central contributor to attenuating cardiometabolic diseases.

Adipose tissue lipid metabolism is a critical regulator of systemic energy balance, but its impact on cardiometabolic health is paradoxical. This review dissects the 2 primary lipolytic systems in adipocytes: the canonical cytosolic pathway driven by ATGL/PNPLA2 (adipose triglyceride lipase) and the lysosomal pathway governed by LAL/LIPA (lysosomal acid lipase). We present emerging evidence that these pathways exert opposing effects in the context of obesity. While excessive fatty acid efflux from dysregulated cytosolic lipolysis is a known driver of adiposopathic dyslipidemia, adipose inflammation, and direct cardiac lipotoxicity, which collectively impair cardiometabolic health, the activity of the lysosomal pathway is emerging as a protective counterbalance. Genetic and pharmacological studies demonstrate that inhibiting cytosolic ATGL is beneficial for metabolic health, whereas enhancing LAL-mediated lipolysis mitigates obesity-related dysfunction. This functional antagonism between cytosolic and lysosomal lipolysis presents a new paradigm in lipid metabolism, suggesting that therapeutic strategies must be pathway-specific. We conclude that selectively inhibiting pathogenic cytosolic lipid release while promoting beneficial lysosomal lipid processing offers a nuanced approach to treating metabolic disease.

Long-chain fatty acids in the blood are prevented from unfettered movement into nonfenestrated tissues or the arterial wall. During fasting, nonesterified FAs are released from adipose tissue into the circulation and bind to albumin, forming a complex >65 kDa, with limited ability to efficiently cross endothelial cell (EC) barriers without a specific receptor. For this reason, nonhepatic tissue distribution of circulating FA parallels EC expression of the FA-binding protein CD36 (cluster of differentiation 36). The deletion of CD36 in ECs reduces nonesterified FA uptake by the heart, muscle, and brown adipose tissue. The other major transport system for FAs is via lipoproteins. Circulating FAs are contained within TRLs (triglyceride-rich lipoproteins), chylomicrons during the postprandial period, and VLDL (very low-density lipoprotein) both postprandially and during fasting. LPL (lipoprotein lipase) on capillary ECs releases FAs from TRLs and likely allows their passage into tissues, in part, via a CD36-independent process. ECs can also internalize lipoprotein particles, followed by the transendothelial movement of lipids. In this review, we will discuss the pathways of EC uptake of FAs from circulation, how this process affects both EC and tissue biology, and the importance of these processes for systemic metabolism and vascular health. We will conclude with speculations on methods to modulate EC FA uptake and their implications for human health.

The delivery of insulin to the skeletal muscle has a major influence on glucose disposal in muscle, where 80% of total body glucose disposal occurs. The skeletal muscle microvascular endothelial cells play a critical role in peripheral insulin sensitivity through their regulation of insulin delivery. Recent advancements in methodologies have provided in-depth views of the molecular mechanisms by which the endothelial cells regulate the delivery process. However, how the cellular machinery is modulated under physiological or pathological conditions remains largely unexplored. Conditions with estrogen deficiency and obesity are 2 situations that are closely associated with peripheral insulin resistance and type 2 diabetes in humans. It is of great interest to determine whether and how endothelial control of insulin delivery impacts the development of metabolic dysregulation under these and other conditions. This review aims to provide an overview of the molecular mechanisms governing insulin delivery to the skeletal muscle. The available evidence will be presented that the transcytosis of insulin across the endothelial cell monolayer in skeletal muscle plays a critical role in muscle insulin delivery, thereby having a major impact on overall glucose homeostasis. In vivo investigations with manipulation of mechanisms in endothelial cells will be summarized, and the current knowledge gaps will be presented. Interrogation of the role of the endothelium in insulin transport provides a paradigm in which insights are being gained about cellular actions of insulin, molecular transport by endothelial cells, and the intricacies of glucose homeostasis.