Myeloid cell–induced angiogenesis: a sticky business

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Aprotinin inhibits proinflammatory activation of endothelial cells by thrombin through the protease-activated receptor 1

ObjectiveThrombin is generated in significant quantities during cardiopulmonary bypass and mediates adverse events, such as platelet aggregation and proinflammatory responses, through activation of the high-affinity thrombin receptor protease-activated receptor 1, which is expressed on platelets and endothelium. Thus antagonism of protease-activated receptor 1 might have broad therapeutic significance. Aprotinin, used clinically to reduce transfusion requirements and the inflammatory response to bypass, has been shown to inhibit protease-activated receptor 1 on platelets in vitro and in vivo. Here we have examined whether aprotinin inhibits endothelial protease-activated receptor 1 activation and resulting proinflammatory responses induced by thrombin.MethodsProtease-activated receptor 1 expression and function were examined in cultured human umbilical vein endothelial cells after treatment with α-thrombin at 0.02 to 0.15 U/mL in the presence or absence of aprotinin (200-1600 kallikrein inhibitory units/mL). Protease-activated receptor 1 activation was assessed by using an antibody, SPAN-12, which detects only the unactivated receptor, and thrombin-mediated calcium fluxes. Other thrombin-dependent inflammatory pathways investigated were phosphorylation of the p42/44 mitogen-activated protein kinase, upregulation of the early growth response 1 transcription factor, and production of the proinflammatory cytokine interleukin 6.ResultsPretreatment of cultured endothelial cells with aprotinin significantly spared protease-activated receptor 1 receptor cleavage (P < .0001) and abrogated calcium fluxes caused by thrombin. Aprotinin inhibited intracellular signaling through p42/44 mitogen-activated protein kinase (P < .05) and early growth response 1 transcription factor (P < .05), as well as interleukin 6 secretion caused by thrombin (P < .005).ConclusionsThis study demonstrates that endothelial cell activation by thrombin and downstream inflammatory responses can be inhibited by aprotinin in vitro through blockade of protease-activated receptor 1. Our results provide a new molecular basis to help explain the anti-inflammatory properties of aprotinin reported clinically

Variation in Rates of Fatal Coronary Heart Disease by Neighborhood Socioeconomic Status: The Atherosclerosis Risk in Communities Surveillance (1992–2002)

Racial and gender disparities in out-of-hospital deaths from coronary heart disease (CHD) have been well-documented, yet disparities by neighborhood socioeconomic status have been less systematically studied in US population-based surveillance efforts

The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/β-catenin signaling.

Blood vessel stability is essential for embryonic development; in the adult, many diseases are associated with loss of vascular integrity. The ETS transcription factor ERG drives expression of VE-cadherin and controls junctional integrity. We show that constitutive endothelial deletion of ERG (Erg(cEC-KO)) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (Erg(iEC-KO)) results in defective physiological and pathological angiogenesis in the postnatal retina and tumors, with decreased vascular stability. ERG controls the Wnt/β-catenin pathway by promoting β-catenin stability, through signals mediated by VE-cadherin and the Wnt receptor Frizzled-4. Wnt signaling is decreased in ERG-deficient endothelial cells; activation of Wnt signaling with lithium chloride, which stabilizes β-catenin levels, corrects vascular defects in Erg(cEC-KO) embryos. Finally, overexpression of ERG in vivo reduces permeability and increases stability of VEGF-induced blood vessels. These data demonstrate that ERG is an essential regulator of angiogenesis and vascular stability through Wnt signaling.This work was funded by grants from the British Heart Foundation (PG/09/096 and RG/11/17/29256). A.V.S. is a recipient of a National Lung and Heart Institute Foundation Studentship. I.M.A. is a recipient of a DOC-fFORTE fellowship of the Austrian Academy of Sciences at the London Research Institute.This paper was published by Cell Press in Developmental Cell (GM Birdsey, AV Shah, N Dufton, LE Reynolds, LO Almagro, Y Yang, IM Aspalter, ST Khan, JC Mason, E Dejana, B Göttgens, K Hodivala-Dilke, Gerhardt, RH Adams, AM Randi, Developmental Cell 2015, 32, 82-96

Endothelial Progenitors: A Consensus Statement on Nomenclature

Endothelial progenitor cell (EPC) nomenclature remains ambiguous and there is a general lack of concordance in the stem cell field with many distinct cell subtypes continually grouped under the term “EPC.” It would be highly advantageous to agree on standards to confirm an endothelial progenitor phenotype and this should include detailed immunophenotyping, potency assays, and clear separation from hematopoietic angiogenic cells which are not endothelial progenitors. In this review, we seek to discourage the indiscriminate use of “EPCs,” and instead propose precise terminology based on defining cellular phenotype and function. Endothelial colony forming cells and myeloid angiogenic cells are examples of two distinct and well‐defined cell types that have been considered EPCs because they both promote vascular repair, albeit by completely different mechanisms of action. It is acknowledged that scientific nomenclature should be a dynamic process driven by technological and conceptual advances; ergo the ongoing “EPC” nomenclature ought not to be permanent and should become more precise in the light of strong scientific evidence. This is especially important as these cells become recognized for their role in vascular repair in health and disease and, in some cases, progress toward use in cell therapy. Stem Cells Translational Medicine 2017;6:1316–132

Deep-sea microbes as tools to refine the rules of innate immune pattern recognition.

The assumption of near-universal bacterial detection by pattern recognition receptors is a foundation of immunology. The limits of this pattern recognition concept, however, remain undefined. As a test of this hypothesis, we determined whether mammalian cells can recognize bacteria that they have never had the natural opportunity to encounter. These bacteria were cultivated from the deep Pacific Ocean, where the genus Moritella was identified as a common constituent of the culturable microbiota. Most deep-sea bacteria contained cell wall lipopolysaccharide (LPS) structures that were expected to be immunostimulatory, and some deep-sea bacteria activated inflammatory responses from mammalian LPS receptors. However, LPS receptors were unable to detect 80% of deep-sea bacteria examined, with LPS acyl chain length being identified as a potential determinant of immunosilence. The inability of immune receptors to detect most bacteria from a different ecosystem suggests that pattern recognition strategies may be defined locally, not globally.R01 AI093589 - NIAID NIH HHS; P30 DK034854 - NIDDK NIH HHS; U19 AI133524 - NIAID NIH HHS; R01 AI147314 - NIAID NIH HHS; R01 AI116550 - NIAID NIH HHS; R37 AI116550 - NIAID NIH HHS; R01 AI123820 - NIAID NIH HHSAccepted manuscrip

Cardiovascular Health and Incident Cardiovascular Disease and Cancer

The American Heart Association's “Simple 7” offers a practical public health conceptualization of cardiovascular health (CVH). CVH predicts incident cardiovascular disease (CVD) in younger populations, but has not been studied in a large, diverse population of aging postmenopausal women. The extent to which CVH predicts cancer in postmenopausal women is unknown

The Transcription Factor ERG Regulates Super-Enhancers Associated with an Endothelial-Specific Gene Expression Program

Rationale: The ETS transcription factor (TF) ERG is essential for endothelial homeostasis, driving expression of lineage genes and repressing pro-inflammatory genes. Loss of ERG expression is associated with diseases including atherosclerosis. ERG’s homeostatic function is lineage-specific, since aberrant ERG expression in cancer is oncogenic. The molecular basis for ERG lineage-specific activity is unknown. Transcriptional regulation of lineage specificity is linked to enhancer clusters (super-enhancers). Objective: To investigate whether ERG regulates endothelial-specific gene expression via super-enhancers. Methods and Results: Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) in human umbilical vein endothelial cells (HUVEC) showed that ERG binds 93% of super-enhancers ranked according to H3K27ac, a mark of active chromatin. These were associated with endothelial genes such as DLL4, CLDN5, VWF and CDH5. Comparison between HUVEC and prostate cancer TMPRSS2:ERG fusion-positive VCaP cells revealed distinctive lineage-specific transcriptome and super-enhancer profiles. At a subset of endothelial super-enhancers (including DLL4 and CLDN5), loss of ERG results in significant reduction in gene expression which correlates with decreased enrichment of H3K27ac and Mediator subunit MED1, and reduced recruitment of acetyltransferase p300. At these super-enhancers, co-occupancy of GATA2 and AP-1 is significantly lower compared to super-enhancers that remained constant following ERG inhibition. These data suggest distinct mechanisms of super-enhancer regulation in EC and highlight the unique role of ERG in controlling a core subset of super-enhancers. Most disease-associated single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) lie within noncoding regions and perturb TF recognition sequences in relevant cell types. Analysis of GWAS data shows significant enrichment of risk variants for CVD and other diseases, at ERG endothelial enhancers and superenhancers. Conclusions: The TF ERG promotes endothelial homeostasis via regulation of lineage-specific enhancers and super-enhancers. Enrichment of CVD-associated SNPs at ERG super-enhancers suggests that ERGdependent transcription modulates disease risk.This work was funded by grants from the British Heart Foundation (RG/11/17/29256; RG/17/4/32662; FS/15/65/32036; PG/17/33/32990) and Cancer Research U

Burnout among psychotherapists: a cross-cultural value survey among 12 European countries during the coronavirus disease pandemic.

The aim of this study was to examine cross-cultural differences, as operationalized by Schwartz's refined theory of basic values, in burnout levels among psychotherapists from 12 European countries during the coronavirus disease (COVID-19) pandemic. We focused on the multilevel approach to investigate if individual- and country-aggregated level values could explain differences in burnout intensity after controlling for sociodemographic, work-related characteristics and COVID-19-related distress among participants. 2915 psychotherapists from 12 countries (Austria, Bulgaria, Cyprus, Finland, Great Britain, Serbia, Spain, Norway, Poland, Romania, Sweden, and Switzerland) participated in this study. The participants completed the Maslach Burnout Inventory-Human Service Survey, the revised version of the Portrait Values Questionnaire, and a survey questionnaire on sociodemographic, work-related factors and the COVID-19 related distress. In general, the lowest mean level of burnout was noted for Romania, whereas the highest mean burnout intensity was reported for Cyprus. Multilevel analysis revealed that burnout at the individual level was negatively related to self-transcendence and openness-to-change but positively related to self-enhancement and conservation values. However, no significant effects on any values were observed at the country level. Male sex, younger age, being single, and reporting higher COVID-19-related distress were significant burnout correlates. Burnout among psychotherapists may be a transcultural phenomenon, where individual differences among psychotherapists are likely to be more important than differences between the countries of their practice. This finding enriches the discussion on training in psychotherapy in an international context and draws attention to the neglected issue of mental health among psychotherapists in the context of their professional functioning