The historical view of vascular smooth muscle cells (VSMCs) in atherosclerosis is that aberrant proliferation of VSMCs promotes plaque formation, but that VSMCs in advanced plaques are entirely ...beneficial, for example preventing rupture of the fibrous cap. However, this view has been based on ideas that there is a homogenous population of VSMCs within the plaque, that can be identified separate from other plaque cells (particularly macrophages) using standard VSMC and macrophage immunohistochemical markers. More recent genetic lineage tracing studies have shown that VSMC phenotypic switching results in less-differentiated forms that lack VSMC markers including macrophage-like cells, and this switching directly promotes atherosclerosis. In addition, VSMC proliferation may be beneficial throughout atherogenesis, and not just in advanced lesions, whereas VSMC apoptosis, cell senescence, and VSMC-derived macrophage-like cells may promote inflammation. We review the effect of embryological origin on VSMC behavior in atherosclerosis, the role, regulation and consequences of phenotypic switching, the evidence for different origins of VSMCs, and the role of individual processes that VSMCs undergo in atherosclerosis in regard to plaque formation and the structure of advanced lesions. We think there is now compelling evidence that a full understanding of VSMC behavior in atherosclerosis is critical to identify therapeutic targets to both prevent and treat atherosclerosis.
Abstract
Vascular smooth muscle cells (VSMCs) are key participants in both early and late-stage atherosclerosis. VSMCs invade the early atherosclerotic lesion from the media, expanding lesions, but ...also forming a protective fibrous cap rich in extracellular matrix to cover the ‘necrotic’ core. Hence, VSMCs have been viewed as plaque-stabilizing, and decreased VSMC plaque content—often measured by expression of contractile markers—associated with increased plaque vulnerability. However, the emergence of lineage-tracing and transcriptomic studies has demonstrated that VSMCs comprise a much larger proportion of atherosclerotic plaques than originally thought, demonstrate multiple different phenotypes in vivo, and have roles that might be detrimental. VSMCs down-regulate contractile markers during atherosclerosis whilst adopting alternative phenotypes, including macrophage-like, foam cell-like, osteochondrogenic-like, myofibroblast-like, and mesenchymal stem cell-like. VSMC phenotypic switching can be studied in tissue culture, but also now in the media, fibrous cap and deep-core region, and markedly affects plaque formation and markers of stability. In this review, we describe the different VSMC plaque phenotypes and their presumed cellular and paracrine functions, the regulatory mechanisms that control VSMC plasticity, and their impact on atherogenesis and plaque stability.
Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages of an atherosclerotic plaque. According to the 'response to injury' and 'vulnerable plaque' hypotheses, contractile ...VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that generate extracellular matrix to form the fibrous cap and hence stabilize plaques. However, lineage-tracing studies have highlighted flaws in the interpretation of former studies, revealing that these studies had underestimated both the content and functions of VSMCs in plaques and have thus challenged our view on the role of VSMCs in atherosclerosis. VSMCs are more plastic than previously recognized and can adopt alternative phenotypes, including phenotypes resembling foam cells, macrophages, mesenchymal stem cells and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this Review, we present the evidence for VSMC plasticity and summarize the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatiotemporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.
SDMtoolbox 2.0 is a software package for spatial studies of ecology, evolution, and genetics. The release of SDMtoolbox 2.0 allows researchers to use the most current ArcGIS software and MaxEnt ...software, and reduces the amount of time that would be spent developing common solutions. The central aim of this software is to automate complicated and repetitive spatial analyses in an intuitive graphical user interface. One core tenant facilitates careful parameterization of species distribution models (SDMs) to maximize each model's discriminatory ability and minimize overfitting. This includes carefully processing of occurrence data, environmental data, and model parameterization. This program directly interfaces with MaxEnt, one of the most powerful and widely used species distribution modeling software programs, although SDMtoolbox 2.0 is not limited to species distribution modeling or restricted to modeling in MaxEnt. Many of the SDM pre- and post-processing tools have 'universal' analogs for use with any modeling software. The current version contains a total of 79 scripts that harness the power of ArcGIS for macroecology, landscape genetics, and evolutionary studies. For example, these tools allow for biodiversity quantification (such as species richness or corrected weighted endemism), generation of least-cost paths and corridors among shared haplotypes, assessment of the significance of spatial randomizations, and enforcement of dispersal limitations of SDMs projected into future climates-to only name a few functions contained in SDMtoolbox 2.0. Lastly, dozens of generalized tools exists for batch processing and conversion of GIS data types or formats, which are broadly useful to any ArcMap user.
1. Statistical tests partitioning community variation into environmental and spatial components have been widely used to test ecological theories and explore the determinants of community structure ...for applied conservation questions. Despite the wide use of these tests, there is considerable debate about their relative effectiveness. 2. We used simulated communities to evaluate the most commonly employed tests that partition community variation: regression on distance matrices and canonical ordination using a third-order polynomial, principal components of neighbour matrices (PCNM) or Moran's eigenvector maps (MEM) to model spatial components. Each test was evaluated under a variety of realistic sampling scenarios. 3. All tests failed to correctly model spatial and environmental components of variation, and in some cases produced biased estimates of the relative importance of components. Regression on distance matrices under-fit the spatial component, and ordination models consistently under-fit the environmental component. The PCNM and MEM approaches often produced inflated R² statistics, apparently as a result of statistical artefacts involving selection of superfluous axes. This problem occurred regardless of the forward-selection technique used. 4. Both sample configuration and the underlying linear model used to analyse species-environment relationships also revealed strong potential to bias results. 5. Synthesis and applications. Several common applications of variation partitioning in ecology now appear inappropriate. These potentially include decisions for community conservation based on inferred relative strengths of niche and dispersal processes, inferred community responses to climate change, and numerous additional analyses that depend on precise results from multivariate variation-partitioning techniques. We clarify the appropriate uses of these analyses in research programmes, and outline potential steps to improve them.
Atherosclerosis is a chronic inflammatory disease of the vascular system and is the leading cause of cardiovascular diseases worldwide. Excessive generation of reactive oxygen species (ROS) leads to ...a state of oxidative stress which is a major risk factor for the development and progression of atherosclerosis. ROS are important for maintaining vascular health through their potent signalling properties. However, ROS also activate pro-atherogenic processes such as inflammation, endothelial dysfunction and altered lipid metabolism. As such, considerable efforts have been made to identify and characterise sources of oxidative stress in blood vessels. Major enzymatic sources of vascular ROS include NADPH oxidases, xanthine oxidase, nitric oxide synthases and mitochondrial electron transport chains. The production of ROS is balanced by ROS-scavenging antioxidant systems which may become dysfunctional in disease, contributing to oxidative stress. Changes in the expression and function of ROS sources and antioxidants have been observed in human atherosclerosis while in vitro and in vivo animal models have provided mechanistic insight into their functions. There is considerable interest in utilising antioxidant molecules to balance vascular oxidative stress, yet clinical trials are yet to demonstrate any atheroprotective effects of these molecules. Here we will review the contribution of ROS and oxidative stress to atherosclerosis and will discuss potential strategies to ameliorate these aspects of the disease.
The Fibromyalgia Impact Questionnaire (FIQ) was developed in the late 1980s by clinicians at Oregon Health & Science University in an attempt to capture the total spectrum of problems related to ...fibromyalgia and the responses to therapy. It was first published in 1991 and since that time has been extensively used as an index of therapeutic efficacy. Overall, it has been shown to have a credible construct validity, reliable test-retest characteristics and a good sensitivity in demonstrating therapeutic change. The original questionnaire was modified in 1997 and 2002, to reflect ongoing experience with the instrument and to clarify the scoring system. The latest version of the FIQ can be found at the web site of the Oregon Fibromyalgia Foundation (www.myalgia.com/FIQ/FIQ). The FIQ has now been translated into eight languages, and the translated versions have shown operating characteristics similar to the English version.
Limited knowledge of the distribution, abundance, and habitat associations of migratory species hinders effective conservation actions. We use Neotropical migratory birds as a model group to compare ...approaches to prioritize land conservation needed to support ≥30% of the global abundances of 117 species. Specifically, we compare scenarios from spatial optimization models to achieve conservation targets by: 1) area requirements for conserving >30% abundance of each species for each week of the year independently vs. combined; 2) including vs. ignoring spatial clustering of species abundance; and 3) incorporating vs. avoiding human-dominated landscapes. Solutions integrating information across the year require 56% less area than those integrating weekly abundances, with additional reductions when shared-use landscapes are included. Although incorporating spatial population structure requires more area, geographical representation among priority sites improves substantially. These findings illustrate that globally-sourced citizen science data can elucidate key trade-offs among opportunity costs and spatiotemporal representation of conservation efforts.
Objective
To characterise vaginal bacterial composition in early pregnancy and investigate its relationship with first and second trimester miscarriages.
Design
Nested case–control study.
Setting
...Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare NHS Trust, London.
Population
161 pregnancies: 64 resulting in first trimester miscarriage, 14 in second trimester miscarriage and 83 term pregnancies.
Methods
Prospective profiling and comparison of vaginal bacteria composition using 16S rRNA gene‐based metataxonomics from 5 weeks’ gestation in pregnancies ending in miscarriage or uncomplicated term deliveries matched for age, gestation and body mass index.
Main outcome measures
Relative vaginal bacteria abundance, diversity and richness. Pregnancy outcomes defined as first or second trimester miscarriage, or uncomplicated term delivery.
Results
First trimester miscarriage associated with reduced prevalence of Lactobacillus spp.‐dominated vaginal microbiota classified using hierarchical clustering analysis (65.6 versus 87.7%; P = 0.005), higher alpha diversity (mean Inverse Simpson Index 2.5 95% confidence interval 1.8–3.0 versus 1.5 1.3–1.7, P = 0.003) and higher richness 25.1 (18.5–31.7) versus 16.7 (13.4–20), P = 0.017), compared with viable pregnancies. This was independent of vaginal bleeding and observable before first trimester miscarriage diagnosis (P = 0.015). Incomplete/complete miscarriage associated with higher proportions of Lactobacillus spp.‐depleted communities compared with missed miscarriage. Early pregnancy vaginal bacterial stability was similar between miscarriage and term pregnancies.
Conclusions
These findings associate the bacterial component of vaginal microbiota with first trimester miscarriage and indicate suboptimal community composition is established in early pregnancy. While further studies are required to elucidate the mechanism, vaginal bacterial composition may represent a modifiable risk factor for first trimester miscarriage.
Tweetable
Vaginal bacterial composition in first trimester miscarriage is associated with reduced Lactobacillus spp. abundance and is independent of vaginal bleeding.
Tweetable
Vaginal bacterial composition in first trimester miscarriage is associated with reduced Lactobacillus spp. abundance and is independent of vaginal bleeding.
Migration through micron-size constrictions has been seen to rupture the nucleus, release nuclear-localized GFP, and cause localized accumulations of ectopic 53BP1—a DNA repair protein. Here, ...constricted migration of two human cancer cell types and primary mesenchymal stem cells (MSCs) increases DNA breaks throughout the nucleoplasm as assessed by endogenous damage markers and by electrophoretic “comet” measurements. Migration also causes multiple DNA repair proteins to segregate away from DNA, with cytoplasmic mis-localization sustained for many hours as is relevant to delayed repair. Partial knockdown of repair factors that also regulate chromosome copy numbers is seen to increase DNA breaks in U2OS osteosarcoma cells without affecting migration and with nucleoplasmic patterns of damage similar to constricted migration. Such depletion also causes aberrant levels of DNA. Migration-induced nuclear damage is nonetheless reversible for wild-type and sub-cloned U2OS cells, except for lasting genomic differences between stable clones as revealed by DNA arrays and sequencing. Gains and losses of hundreds of megabases in many chromosomes are typical of the changes and heterogeneity in bone cancer. Phenotypic differences that arise from constricted migration of U2OS clones are further illustrated by a clone with a highly elongated and stable MSC-like shape that depends on microtubule assembly downstream of the transcription factor GATA4. Such changes are consistent with reversion to a more stem-like state upstream of cancerous osteoblastic cells. Migration-induced genomic instability can thus associate with heritable changes.
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•Constricted migration causes mis-localization of DNA repair proteins and DNA breaks•Depletion of repair factors leads to DNA damage and chromosomal aberrations•Migration of cancer clones through small pores causes lasting genomic heterogeneity•Gene dosage effects in the transcriptome can perturb cell shape and motility
Irianto et al. demonstrate that cell migration through micron-size constrictions leads to transient DNA damage and cytoplasmic mis-localization of multiple DNA repair factors, with lasting genomic heterogeneity that translate to phenotypic changes. Migration-induced genomic instability can thus associate with heritable changes.
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