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Circulation Research Jul 2020The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive... (Meta-Analysis)
Meta-Analysis Review
The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single-cell RNA sequencing and 2 mass cytometry studies. In a comprehensive meta-analysis, we confirm 4 known macrophage subsets-resident, inflammatory, interferon-inducible cell, and Trem2 (triggering receptor expressed on myeloid cells-2) foamy macrophages-and identify a new macrophage subset resembling cavity macrophages. We also find that monocytes, neutrophils, dendritic cells, natural killer cells, innate lymphoid cells-2, and CD (cluster of differentiation)-8 T cells form prominent and separate immune cell populations in atherosclerotic aortas. Many CD4 T cells express IL (interleukin)-17 and the chemokine receptor CXCR (C-X-C chemokine receptor)-6. A small number of regulatory T cells and T helper 1 cells is also identified. Immature and naive T cells are present in both healthy and atherosclerotic aortas. Our meta-analysis overcomes limitations of individual studies that, because of their experimental approach, over- or underrepresent certain cell populations. Mass cytometry studies demonstrate that cell surface phenotype provides valuable information beyond the cell transcriptomes. The present analysis helps resolve some long-standing controversies in the field. First, Trem2 foamy macrophages are not proinflammatory but interferon-inducible cell and inflammatory macrophages are. Second, about half of all foam cells are smooth muscle cell-derived, retaining smooth muscle cell transcripts rather than transdifferentiating to macrophages. Third, , which had been considered specific for platelets and megakaryocytes, is also prominently expressed in the main population of resident vascular macrophages. Fourth, a new type of resident macrophage shares transcripts with cavity macrophages. Finally, the discovery of a prominent innate lymphoid cell-2 cluster links the single-cell RNA sequencing work to recent flow cytometry data suggesting a strong atheroprotective role of innate lymphoid cells-2. This resolves apparent discrepancies regarding the role of T helper 2 cells in atherosclerosis based on studies that predated the discovery of innate lymphoid cells-2 cells.
Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Biomarkers; Disease Models, Animal; Flow Cytometry; Leukocytes; Phenotype; Plaque, Atherosclerotic; RNA-Seq; Single-Cell Analysis; Transcriptome
PubMed: 32673538
DOI: 10.1161/CIRCRESAHA.120.316903 -
Circulation Research Oct 2018Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the...
RATIONALE
Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the pathophysiology of atherosclerotic disease, we need to understand the characteristics of lipid-laden foamy macrophages in the subintimal space during atherosclerosis.
OBJECTIVE
We sought to examine the transcriptomic profiles of foamy and nonfoamy macrophages isolated from atherosclerotic intima.
METHODS AND RESULTS
Single-cell RNA sequencing analysis of CD45 leukocytes from murine atherosclerotic aorta revealed that there are macrophage subpopulations with distinct differentially expressed genes involved in various functional pathways. To specifically characterize the intimal foamy macrophages of plaque, we developed a lipid staining-based flow cytometric method for analyzing the lipid-laden foam cells of atherosclerotic aortas. We used the fluorescent lipid probe BODIPY493/503 and assessed side-scattered light as an indication of cellular granularity. BODIPYSSC foamy macrophages were found residing in intima and expressing CD11c. Foamy macrophage accumulation determined by flow cytometry was positively correlated with the severity of atherosclerosis. Bulk RNA sequencing analysis showed that compared with nonfoamy macrophages, foamy macrophages expressed few inflammatory genes but many lipid-processing genes. Intimal nonfoamy macrophages formed the major population expressing IL (interleukin)-1β and many other inflammatory transcripts in atherosclerotic aorta.
CONCLUSIONS
RNA sequencing analysis of intimal macrophages from atherosclerotic aorta revealed that lipid-loaded plaque macrophages are not likely the plaque macrophages that drive lesional inflammation.
Topics: Animals; Aorta; Cells, Cultured; Humans; Macrophages; Male; Mice; Mice, Inbred C57BL; Plaque, Atherosclerotic; Transcriptome
PubMed: 30359200
DOI: 10.1161/CIRCRESAHA.118.312804 -
Circulation Jul 2019The cells that form the arterial wall contribute to multiple vascular diseases. The extent of cellular heterogeneity within these populations has not been fully...
BACKGROUND
The cells that form the arterial wall contribute to multiple vascular diseases. The extent of cellular heterogeneity within these populations has not been fully characterized. Recent advances in single-cell RNA-sequencing make it possible to identify and characterize cellular subpopulations.
METHODS
We validate a method for generating a droplet-based single-cell atlas of gene expression in a normal blood vessel. Enzymatic dissociation of 4 whole mouse aortas was followed by single-cell sequencing of >10 000 cells.
RESULTS
Clustering analysis of gene expression from aortic cells identified 10 populations of cells representing each of the main arterial cell types: fibroblasts, vascular smooth muscle cells, endothelial cells (ECs), and immune cells, including monocytes, macrophages, and lymphocytes. The most significant cellular heterogeneity was seen in the 3 distinct EC populations. Gene set enrichment analysis of these EC subpopulations identified a lymphatic EC cluster and 2 other populations more specialized in lipoprotein handling, angiogenesis, and extracellular matrix production. These subpopulations persist and exhibit similar changes in gene expression in response to a Western diet. Immunofluorescence for Vcam1 and Cd36 demonstrates regional heterogeneity in EC populations throughout the aorta.
CONCLUSIONS
We present a comprehensive single-cell atlas of all cells in the aorta. By integrating expression from >1900 genes per cell, we are better able to characterize cellular heterogeneity compared with conventional approaches. Gene expression signatures identify cell subpopulations with vascular disease-relevant functions.
Topics: Animals; Aorta; Endothelial Cells; Female; Gene Expression Profiling; Mice; Mice, Inbred C57BL; Single-Cell Analysis
PubMed: 31146585
DOI: 10.1161/CIRCULATIONAHA.118.038362 -
Journal of Vascular Surgery Feb 2022
Topics: Aorta; Blood Vessel Prosthesis; Humans
PubMed: 35067328
DOI: 10.1016/j.jvs.2021.09.053 -
Journal of Vascular Surgery Aug 2022Abdominal aortic coarctation and hypoplasia are uncommon diseases, recognized most often in pediatric-aged individuals. Comprehensive studies regarding the pathologic... (Review)
Review
OBJECTIVES
Abdominal aortic coarctation and hypoplasia are uncommon diseases, recognized most often in pediatric-aged individuals. Comprehensive studies regarding the pathologic spectrum of these aortopathies are nonexistent. This investigation was undertaken to better define the histologic and morphologic character of abdominal aortic narrowings affecting children and assess its potential relevance to contemporary clinical practice.
METHODS
Aortic specimens obtained during open operations in children being treated for symptomatic, noninflammatory abdominal aortic narrowings at the University of Michigan were subjected to histologic study after hematoxylin and eosin, Movat, Verhoeff Van Gieson, and Masson's trichrome preparations. Microscopic findings were correlated with the anatomic aortic images. In addition, a detailed review was completed of all prior reports in the English literature that included images depicting the histologic character of noninflammatory abdominal aortic narrowings in children.
RESULTS
Among a series of 67 pediatric-aged individuals undergoing open surgical interventions for abdominal aortic narrowings, eight children ranging in age from 9 months to 18 years, had adequate aortic tissue available for study. The loci of the specimens paralleled the anatomic sites of segmental coarctations observed in the entire series, with involvement of the suprarenal abdominal aorta (n = 3), intrarenal aorta (n = 2), and infrarenal aorta (n = 1). Diffusely hypoplastic abdominal aortas (n = 2) included one case of a de facto aortic duplication, represented by a channel that paralleled the narrow native aorta and gave origin to celiac artery branches, as well as the superior mesenteric and renal arteries. Concentric or eccentric intimal fibroplasia was observed in every aorta, often with internal elastic fragmentation and duplication (n = 4). Media abnormalities included elastic tissue disorganization (n = 3) and focal medial fibrosis (n = 1). Organizing luminal thrombus occurred in two infants. Coexistent ostial stenoses of the celiac, superior mesenteric, or renal arteries were observed in all but the only child who had an infrarenal aortic coarctation. Neurofibromatosis type 1 affected one child whose histologic findings were indistinguishable from those of the other children. A review of prior published histologic images of abdominal aortic coarctation and hypoplasia affecting children from other centers revealed a total of 14 separate reports, each limited to single case photomicrographs, of which 11 exhibited intimal fibroplasia.
CONCLUSIONS
Intimal fibroplasia is a common accompaniment of developmental abdominal aortic coarctation and hypoplasia. It is posited that intimal fibroplasia, which is likely progressive in instances of abnormal shear stresses in these diminutive vessels, may contribute to less salutary outcomes after endovascular and certain open reconstructions of pediatric abdominal aortic narrowings.
Topics: Adolescent; Aorta, Abdominal; Aortic Coarctation; Child; Child, Preschool; Humans; Infant; Plastic Surgery Procedures
PubMed: 35149163
DOI: 10.1016/j.jvs.2022.01.121 -
Annals of Biomedical Engineering Jan 2015The non-uniform distribution of atherosclerosis within the arterial system has been attributed to pro-atherogenic influences of low, oscillatory haemodynamic wall shear... (Review)
Review
The non-uniform distribution of atherosclerosis within the arterial system has been attributed to pro-atherogenic influences of low, oscillatory haemodynamic wall shear stress (WSS) on endothelial cells (EC). This theory is challenged by the changes in lesion location that occur with age in human and rabbit aortas. Furthermore, a number of point-wise comparisons of lesion prevalence and WSS have failed to support it. Here we investigate the hypothesis that multidirectional flow-characterized as the average magnitude of WSS components acting transversely to the mean vector (transWSS)-plays a key role. Maps of lesion prevalence around aortic branch ostia in immature and mature rabbits were compared with equivalent maps of time average WSS, the OSI (an index characterizing oscillatory flow) and transWSS, obtained from computational simulations; Spearman's rank correlation coefficients were calculated for aggregated data and 95% confidence intervals were obtained by bootstrapping methods. Lesion prevalence correlated positively, strongly and significantly with transWSS at both ages. Correlations of lesion prevalence with the other shear metrics were not significant or were significantly lower than those obtained for transWSS. No correlation supported the low, oscillatory WSS theory. The data are consistent with the view that multidirectional near-wall flow is highly pro-atherogenic. Effects of multidirectional flow on EC, and methods for investigating them, are reviewed. The finding that oscillatory flow has pro-inflammatory effects when acting perpendicularly to the long axis of EC but anti-inflammatory effects when acting parallel to it may explain the stronger correlation of lesion prevalence with transWSS than with the OSI.
Topics: Animals; Aorta; Atherosclerosis; Biomechanical Phenomena; Hemorheology; Humans; Hydrodynamics; Male; Rabbits
PubMed: 25138165
DOI: 10.1007/s10439-014-1095-4 -
Hellenic Journal of Cardiology : HJC =... 2015
Topics: Aorta; Aortic Valve; Bioprosthesis; Humans; Models, Cardiovascular; Transcatheter Aortic Valve Replacement
PubMed: 26429372
DOI: No ID Found -
Acta Biomaterialia Sep 2023The mechanics of vascular tissue, particularly its fracture properties, are crucial in the onset and progression of vascular diseases. Vascular tissue properties are...
The mechanics of vascular tissue, particularly its fracture properties, are crucial in the onset and progression of vascular diseases. Vascular tissue properties are complex, and the identification of fracture mechanical properties relies on robust and efficient numerical tools. In this study, we propose a parameter identification pipeline to extract tissue properties from force-displacement and digital image correlation (DIC) data. The data has been acquired by symconCT testing porcine aorta wall specimens. Vascular tissue is modelled as a non-linear viscoelastic isotropic solid, and an isotropic cohesive zone model describes tissue fracture. The model closely replicated the experimental observations and identified the fracture energies of 1.57±0.82 kJ m and 0.96±0.34 kJ m for rupturing the porcine aortic media along the circumferential and axial directions, respectively. The identified strength was always below 350 kPa, a value significantly lower than identified through classical protocols, such as simple tension, and sheds new light on the resilience of the aorta. Further refinements to the model, such as considering rate effects in the fracture process zone and tissue anisotropy, could have improved the simulation results. STATEMENT OF SIGNIFICANCE: This paper identified porcine aorta's biomechanical properties using data acquired through a previously developed experimental protocol, the symmetry-constraint compact tension test. An implicit finite element method model mimicked the test, and a two-step approach identified the material's elastic and fracture properties directly from force-displacement curves and digital image correlation-based strain measurements. Our findings show a lower strength of the abdominal aorta as compared to the literature, which may have significant implications for the clinical evaluation of the risk of aortic rupture.
Topics: Swine; Animals; Biomechanical Phenomena; Aorta, Abdominal; Mechanical Phenomena; Aortic Rupture; Computer Simulation; Stress, Mechanical; Finite Element Analysis
PubMed: 37422007
DOI: 10.1016/j.actbio.2023.06.020 -
The Journal of Surgical Research Jul 2023Ascending aortic dilatation is a well-known risk factor for aortic rupture. Indications for aortic replacement in its dilatation concomitant to other open-heart surgery...
INTRODUCTION
Ascending aortic dilatation is a well-known risk factor for aortic rupture. Indications for aortic replacement in its dilatation concomitant to other open-heart surgery exist; however, cut-off values based solely on aortic diameter may fail to identify patients with weakened aortic tissue. We introduce near-infrared spectroscopy (NIRS) as a diagnostic tool to nondestructively evaluate the structural and compositional properties of the human ascending aorta during open-heart surgeries. During open-heart surgery, NIRS could provide information regarding tissue viability in situ and thus contribute to the decision of optimal surgical repair.
MATERIALS AND METHODS
Samples were collected from patients with ascending aortic aneurysm (n = 23) undergoing elective aortic reconstruction surgery and from healthy subjects (n = 4). The samples were subjected to spectroscopic measurements, biomechanical testing, and histological analysis. The relationship between the near-infrared spectra and biomechanical and histological properties was investigated by adapting partial least squares regression.
RESULTS
Moderate prediction performance was achieved with biomechanical properties (r = 0.681, normalized root-mean-square error of cross-validation = 17.9%) and histological properties (r = 0.602, normalized root-mean-square error of cross-validation = 22.2%). Especially the performance with parameters describing the aorta's ultimate strength, for example, failure strain (r = 0.658), and elasticity (phase difference, r = 0.875) were promising and could, therefore, provide quantitative information on the rupture sensitivity of the aorta. For the estimation of histological properties, the results with α-smooth muscle actin (r = 0.581), elastin density (r = 0.973), mucoid extracellular matrix accumulation(r = 0.708), and media thickness (r = 0.866) were promising.
CONCLUSIONS
NIRS could be a potential technique for in situ evaluation of biomechanical and histological properties of human aorta and therefore useful in patient-specific treatment planning.
Topics: Humans; Spectroscopy, Near-Infrared; Aorta; Aortic Aneurysm; Aortic Diseases; Elasticity; Biomechanical Phenomena
PubMed: 36870305
DOI: 10.1016/j.jss.2023.01.016 -
Journal of Cardiovascular Translational... Oct 2022Aortic surgeries in congenital conditions, such as hypoplastic left heart syndrome (HLHS), aim to restore and maintain the conduit and reservoir functions of the aorta....
Aortic surgeries in congenital conditions, such as hypoplastic left heart syndrome (HLHS), aim to restore and maintain the conduit and reservoir functions of the aorta. We proposed a method to assess these two functions based on 4D flow MRI, and we applied it to study the aorta in pre-Fontan HLHS. Ten pre-Fontan HLHS patients and six age-matched controls were studied to derive the advective pressure difference and viscous dissipation for conduit function, and pulse wave velocity and elastic modulus for reservoir function. The reconstructed neo-aorta in HLHS subjects achieved a good conduit function at a cost of an impaired reservoir function (69.7% increase of elastic modulus). The native descending HLHS aorta displayed enhanced reservoir (elastic modulus being 18.4% smaller) but impaired conduit function (three-fold increase in peak advection). A non-invasive and comprehensive assessment of aortic conduit and reservoir functions is feasible and has potentially clinical relevance in congenital vascular conditions.
Topics: Humans; Aorta, Thoracic; Pulse Wave Analysis; Hypoplastic Left Heart Syndrome; Aorta
PubMed: 35199256
DOI: 10.1007/s12265-022-10221-4