| 1. |
- Aldi, Silvia, et al.
(författare)
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Dual roles of heparanase in human carotid plaque calcification
- 2019
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Ingår i: Atherosclerosis. - : ELSEVIER IRELAND LTD. - 0021-9150 .- 1879-1484. ; 283, s. 127-136
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-beta-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of HPSE is controversial in osteogenesis and bone remodeling while it is unexplored in vascular calcification. Previously, we reported upregulation of HPSE in human carotid endarterectomies from symptomatic patients and showed correlation of HPSE expression with markers of inflammation and increased thrombogenicity. The present aim is to investigate HPSE expression in relation to genes associated with osteogenesis and osteolysis and the effect of elevated HPSE expression on calcification and osteolysis in vitro.Methods: Transcriptomic and immunohistochemical analyses were performed using the Biobank of Karolinska Endarterectomies (BiKE). In vitro calcification and osteolysis were analysed in human carotid smooth muscle cells overexpressing HPSE and bone marrow-derived osteoclasts from HPSE-transgenic mice respectively.Results: HPSE expression correlated primarily with genes coupled to osteoclast differentiation and function in human carotid atheromas. HPSE was expressed in osteoclast-like cells in atherosclerotic lesions, and HPSE-transgenic bone marrow-derived osteoclasts displayed a higher osteolytic activity compared to wild-type cells. Contrarily, human carotid SMCs with an elevated HPSE expression demonstrated markedly increased mineralization upon osteogenic differentiation.Conclusions: We suggest that HPSE may have dual functions in vascular calcification, depending on the stage of the disease and presence of inflammatory cells. While HPSE plausibly enhances mineralization and osteogenic differentiation of vascular smooth muscle cells, it is associated with inflammation-induced osteoclast differentiation and activity in advanced atherosclerotic plaques.
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| 2. |
- Chemaly, Melody, et al.
(författare)
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Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis
- 2023
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Ingår i: Biomolecules. - : MDPI AG. - 2218-273X. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH. Objective: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting. Methods: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study (n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Results: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 & PLUSMN; 693.21 vs. 520.94 & PLUSMN; 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 & PLUSMN; 928.49 vs. 582.07 & PLUSMN; 545.34 MFI, HR = 1.600, CI [1.092-2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 & PLUSMN; 258.73 vs. 1752 & PLUSMN; 366.84 MFI; p = 0.004). Conclusions: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability.
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| 3. |
- Karlöf, Eva, et al.
(författare)
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Correlation of computed tomography with carotid plaque transcriptomes associates calcification with lesion-stabilization
- 2019
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Ingår i: Atherosclerosis. - Stockholm : ELSEVIER IRELAND LTD. - 0021-9150 .- 1879-1484. ; 288, s. 175-185
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. We recently found enrichment of genes associated with calcification in carotid plaques from asymptomatic patients. Here, we hypothesized that calcification represents a stabilising feature of plaques and investigated how macro-calcification, as estimated by computed tomography (CT), correlates with gene expression profiles in lesions. Methods: Plaque calcification was measured in pre-operative CT angiographies. Plaques were sorted into high- and low-calcified, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry and qPCR were performed to evaluate the findings in plaques and arteries with medial calcification from chronic kidney disease patients. Results: Smooth muscle cell (SMC) markers were upregulated in high-calcified plaques and calcified plaques from symptomatic patients, whereas macrophage markers were downregulated. The most enriched processes in high-calcified plaques were related to SMCs and extracellular matrix (ECM) organization, while inflammation, lipid transport and chemokine signaling were repressed. These findings were confirmed in arteries with high medial calcification. Proteoglycan 4 (PRG4) was identified as the most upregulated gene in association with plaque calcification and found in the ECM, SMA+ and CD68+/TRAP + cells. Conclusions: Macro-calcification in carotid lesions correlated with a transcriptional profile typical for stable plaques, with altered SMC phenotype and ECM composition and repressed inflammation. PRG4, previously not described in atherosclerosis, was enriched in the calcified ECM and localized to activated macrophages and smooth muscle-like cells. This study strengthens the notion that assessment of calcification may aid evaluation of plaque phenotype and stroke risk.
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| 4. |
- Kronqvist Håård, Malin
(författare)
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Government steering and government disruption : co-operation between government and municipal actors in a state-initiated school improvement programme from the municipal actors’ perspective
- 2023
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Ingår i: Nordic Journal of Studies in Educational Policy. - : Routledge. - 2002-0317. ; 9:2, s. 113-125
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Tidskriftsartikel (refereegranskat)abstract
- This article focuses on the co-operation between the Swedish National Agency for Education and school actors at the municipal level, examined from the latter’s perspective, within the context of a state-initiated school improvement programme, namely Co-operation for the Best School Possible (CBS). Co-operation between different levels of the school system is a neglected but essential aspect to analyse in a decentralised system such as Sweden’s, which is showing signs of re-centralisation. Empirically, the article is based on interviews with local actors in a small municipality participating in CBS. The interviews were part of a case study, and the analysis was guided by the theory of soft governance, Vedung’s concepts of sticks, carrots, and sermons as policy instruments, and Weick’s concept of sensemaking. Sensemaking, evident in the case study as a retrospective communicative notion, was employed to capture the local actors’ stories of how they perceived CBS. The connection with past experiences also played a part in their sensemaking since a clear history exists and was noted between the state and municipal levels. In conclusion, the analysis shows that CBS used sticks, carrots and sermons to steer municipal school actors towards the right path as regards school improvement. © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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| 5. |
- Kronqvist Håård, Malin
(författare)
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School Leaders’ Response to Neoliberal Education Reforms : A Scoping Review
- 2024
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Tidskriftsartikel (refereegranskat)abstract
- The aim with this scoping review is to provide an overview of research on school leaders’ response to neoliberal education reform. There have been claims that there is a lack of empirical research critically examining the vast amounts of education reforms from a local perspective This review is an answer to that call, as it analyses existing research on school leaders’ experience of neoliberal reforms using empirical data. This article employs a resistance theory perspective. The search resulted in 21 articles that met all the inclusion criteria. A descriptive analysis and a content analysis was undertaken. The latter considers how school leaders navigate the reforms, and also how they resisted them. The results show that resistance was manifested in terms such as speaking your mind, irony, simulation and compliance. The reviewed studies exemplify some of the problems of the ‘new professionalism’ fashioned by educational policy seeking to steer the work of schools in a competitive school marketplace. Overall, the review underscores the transformative nature of educational reforms on education and the imperative for using resistance and power theories to both help shed light on the sometimes soul altering changes these initiatives can achieve and point to possible counter-discourse and counter-conduct.
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| 6. |
- Kronqvist Håård, Malin
(författare)
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Styrning genom samverkan? – En textanalys av dominerande diskurser i en statlig skolförbättringssatsning
- 2021
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Ingår i: Pedagogisk forskning i Sverige. - : Linnaeus University. - 1401-6788 .- 2001-3345. ; 26:1, s. 42-69
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Tidskriftsartikel (refereegranskat)abstract
- Artikeln tar sin utgångspunkt i tre texter rörande skolförbättringssatsningen Samverkan för bästa skola (SBS) varav två kan betecknas som policytexter och den tredje är en myndighets hemsida rörande SBS. Policydiskurser är viktiga att undersöka i och med att de ramar in vad som är den politiska viljan kring ett givet fenomen. Genom policy konstrueras mening och identifieras problem i utbildning. Syftet med studien är att skriva fram ett tänkbart narrativ om SBS för att synliggöra och lyfta fram underliggande diskurser i retoriken kring SBS i de analyserade texterna. Analysen har guidats av både en narrativ och en diskursiv ansats. Ett styrningsperspektiv har anlagts i analysen med utgångspunkt i governance och governmentality. I analysen lyfts olika konkurrerande diskurser fram spänningen mellan samverkan och styrning, mellan decentralisering och kontroll. Studiens kunskapsbidrag är att den kritiskt granskar en av de största skolutvecklingssatsningar som gjorts i svensk skola och ett resonemang om de underliggande antaganden som identifierats i analysen förs. Att vara kritisk betyder inte att säga hur saker egentligen är, utan vad diskursanalyser av detta slag kan bidra med är att lyfta blicken från dessa under-liggande common sense-antaganden som genomsyrar offentliga texter och på så sätt öppna upp för alternativa tankesätt och handlingssätt.
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| 7. |
- Kronqvist Håård, Malin
(författare)
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Technologies of Power in a State-initiated School Improvement Programme : Governing by school self-improvement
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis investigates the power dynamics between state and municipal actors within the state-initiated school improvement program, Co-operation for the Best School Possible (CBS). CBS can be seen as an example of the numerous reforms driven by the global education reform movement (GERM), which is rooted in neoliberal ideologies. The thesis aims to illuminate how power operates within the CBS program, focusing on the construction and regulation of local school actors. It explores the intricate power relations between the Swedish National Agency for Education (SNAE) and local school actors, including headteachers, local education authorities and local politicians.A Foucauldian perspective serves as the overarching analytical framework, incorporating key concepts such as governmentality, sovereign, disciplinary, and pastoral power, along with neoliberalism, discourse, and resistance. The study also employs soft governance and policy instruments. The research adopts a case study approach, utilising data collected through interviews, meeting observations, and documents from a municipality, as well as national policy documents. The analysis methods include narrative discourse analysis, thematic analyses, and a scoping review.The findings underscore the constitutive role of language in official policy texts and how local actors are governed through policy instruments such as carrots, sticks, and sermons. From a Foucauldian perspective, local school actors are identified as deviant under the normalising gaze of experts, internalising state-imposed norms and standards. Subtler methods of steering involve pastoral techniques, such as self-evaluation, requiring local actors to reflect on their weaknesses and how to better themselves. The Systematic Quality Assurance (SQA) work exemplifies a self-monitoring trend in education, where schools continuously self-evaluate based on preset standards, combining disciplinary, sovereign, and pastoral power to improve performance. The SNAE functions as both a monitor and a pastor, providing the local actors with a roadmap to redemption.Eight years after CBS’s implementation, research on its various aspects remains limited. This thesis contributes to understanding how power technologies operate in large-scale school improvement initiatives like CBS. It addresses gaps in existing research by examining how power functions in public education and how neoliberal reforms shape the professional identities and practices of local school actors.
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| 8. |
- Kronqvist Håård, Malin
(författare)
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The Quest for Continuous Improvement in Light of Power : Disciplinary, Sovereign and Pastoral Power in a State-initiated School Improvement Programme
- 2024
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Tidskriftsartikel (refereegranskat)abstract
- There is a global movement of education reform, informed by a neoliberal agenda, emphasising continuous improvement, and accountability through performance measurements, surveillance and monitoring. This puts local school actors under a constant gaze and endless pressure to perform. This article uses a Swedish state-initiated school improvement programme, Co-operation for the Best School Possible (CBS), to investigate how power is exercised within the programme and to discuss possible implications for the local actors. A theoretical model based on Foucault’s power modes of sovereign, disciplinary and pastoral power as well as governmentality is used. Empirically the article builds on a case study from a municipality participating in CBS. The analysis takes impression of Jackson and Mazzei’s ‘thinking with theory’. The CBS programme illustrates the widespread and multifaceted nature of power in educational governance, prompting local actors to internalise norms, self-regulate, and continuously evaluate their practices. This study highlights the importance of understanding the interplay of different power modes in shaping educational practices and the professional lives of local school actors. This article has contributed to questioning the common sensical, and it has made the exercises of power recognisable through the use of Foucault’s concepts.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Rykaczewska, Urszula, et al.
(författare)
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PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling
- 2020
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Ingår i: Circulation Research. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7330 .- 1524-4571. ; 126:5, s. 571-585
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: PCSKs (Proprotein convertase subtilisins/kexins) are a protease family with unknown functions in vasculature. Previously, we demonstrated PCSK6 upregulation in human atherosclerotic plaques associated with smooth muscle cells (SMCs), inflammation, extracellular matrix remodeling, and mitogens. Objective: Here, we applied a systems biology approach to gain deeper insights into the PCSK6 role in normal and diseased vessel wall. Methods and Results: Genetic analyses revealed association of intronic PCSK6 variant rs1531817 with maximum internal carotid intima-media thickness progression in high-cardiovascular risk subjects. This variant was linked with PCSK6 mRNA expression in healthy aortas and plaques but also with overall plaque SMA+ cell content and pericyte fraction. Increased PCSK6 expression was found in several independent human cohorts comparing atherosclerotic lesions versus healthy arteries, using transcriptomic and proteomic datasets. By immunohistochemistry, PCSK6 was localized to fibrous cap SMA+ cells and neovessels in plaques. In human, rat, and mouse intimal hyperplasia, PCSK6 was expressed by proliferating SMA+ cells and upregulated after 5 days in rat carotid balloon injury model, with positive correlation to PDGFB (platelet-derived growth factor subunit B) and MMP (matrix metalloprotease) 2/MMP14. Here, PCSK6 was shown to colocalize and cointeract with MMP2/MMP14 by in situ proximity ligation assay. Microarrays of carotid arteries from Pcsk6(-/-) versus control mice revealed suppression of contractile SMC markers, extracellular matrix remodeling enzymes, and cytokines/receptors. Pcsk6(-/-) mice showed reduced intimal hyperplasia response upon carotid ligation in vivo, accompanied by decreased MMP14 activation and impaired SMC outgrowth from aortic rings ex vivo. PCSK6 silencing in human SMCs in vitro leads to downregulation of contractile markers and increase in MMP2 expression. Conversely, PCSK6 overexpression increased PDGFBB (platelet-derived growth factor BB)-induced cell proliferation and particularly migration. Conclusions: PCSK6 is a novel protease that induces SMC migration in response to PDGFB, mechanistically via modulation of contractile markers and MMP14 activation. This study establishes PCSK6 as a key regulator of SMC function in vascular remodeling.
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| 13. |
- Röhl, Samuel, et al.
(författare)
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Transcriptomic profiling of experimental arterial injury reveals new mechanisms and temporal dynamics in vascular healing response
- 2020
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Ingår i: JVS-Vascular Science. - : Elsevier BV. - 2666-3503. ; 315, s. E14-E14
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Endovascular interventions cause arterial injury and induce a healing response to restore vessel wall homeostasis. Complications of defective or excessive healing are common and result in increased morbidity and repeated interventions. Experimental models of intimal hyperplasia are vital for understanding the vascular healing mechanisms and resolving the clinical problems of restenosis, vein graft stenosis, and dialysis access failure. Our aim was to systematically investigate the transcriptional, histologic, and systemic reaction to vascular injury during a prolonged time. Methods: Balloon injury of the left common carotid artery was performed in male rats. Animals (n = 69) were euthanized before or after injury, either directly or after 2 hours, 20 hours, 2 days, 5 days, 2 weeks, 6 weeks, and 12 weeks. Both injured and contralateral arteries were subjected to microarray profiling, followed by bioinformatic exploration, histologic characterization of the biopsy specimens, and plasma lipid analyses. Results: Immune activation and coagulation were key mechanisms in the early response, followed by cytokine release, tissue remodeling, and smooth muscle cell modulation several days after injury, with reacquisition of contractile features in later phases. Novel pathways related to clonal expansion, inflammatory transformation, and chondro-osteogenic differentiation were identified and immunolocalized to neointimal smooth muscle cells. Analysis of uninjured arteries revealed a systemic component of the reaction after local injury, underlined by altered endothelial signaling, changes in overall tissue bioenergy metabolism, and plasma high-density lipoprotein levels. Conclusions: We demonstrate that vascular injury induces dynamic transcriptional landscape and metabolic changes identifiable as early, intermediate, and late response phases, reaching homeostasis after several weeks. This study provides a temporal “roadmap” of vascular healing as a publicly available resource for the research community.
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| 14. |
- Seime, Till, et al.
(författare)
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Biomechanical Assessment of Macro-Calcification in Human Carotid Atherosclerosis and Its Impact on Smooth Muscle Cell Phenotype
- 2022
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 11:20, s. 3279-
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Tidskriftsartikel (refereegranskat)abstract
- Intimal calcification and vascular stiffening are predominant features of end-stage atherosclerosis. However, their role in atherosclerotic plaque instability and how the extent and spatial distribution of calcification influence plaque biology remain unclear. We recently showed that extensive macro calcification can be a stabilizing feature of late-stage human lesions, associated with a reacquisition of more differentiated properties of plaque smooth muscle cells (SMCs) and extracellular matrix (ECM) remodeling. Here, we hypothesized that biomechanical forces related to macro-calcification within plaques influence SMC phenotype and contribute to plaque stabilization. We generated a finite element modeling (FEM) pipeline to assess plaque tissue stretch based on image analysis of preoperative computed tomography angiography (CTA) of carotid atherosclerotic plaques to visualize calcification and soft tissues (lipids and extracellular matrix) within the lesions. Biomechanical stretch was significantly reduced in tissues in close proximity to macro calcification, while increased levels were observed within distant soft tissues. Applying this data to an in vitro stretch model on primary vascular SMCs revealed upregulation of typical markers for differentiated SMCs and contractility under low stretch conditions but also impeded SMC alignment. In contrast, high stretch conditions in combination with calcifying conditions induced SMC apoptosis. Our findings suggest that the load bearing capacities of macro calcifications influence SMC differentiation and survival and contribute to atherosclerotic plaque stabilization.
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| 15. |
- Skenteris, Nikolaos T, et al.
(författare)
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Osteomodulin attenuates smooth muscle cell osteogenic transition in vascular calcification
- 2022
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Ingår i: Clinical and Translational Medicine. - : Wiley. - 2001-1326. ; 12:2, s. 1-22
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Vascular calcification is a prominent feature of late-stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in patients reported that plasma levels of osteomodulin (OMD), a proteoglycan involved in bone mineralisation, associate with diabetes and CVD. We hypothesised that OMD could be implicated in these diseases via vascular calcification as a common underlying factor and aimed to investigate its role in this context.METHODS AND RESULTS: In patients with chronic kidney disease, plasma OMD levels correlated with markers of inflammation and bone turnover, with the protein present in calcified arterial media. Plasma OMD also associated with cardiac calcification and the protein was detected in calcified valve leaflets by immunohistochemistry. In patients with carotid atherosclerosis, circulating OMD was increased in association with plaque calcification as assessed by computed tomography. Transcriptomic and proteomic data showed that OMD was upregulated in atherosclerotic compared to control arteries, particularly in calcified plaques, where OMD expression correlated positively with markers of smooth muscle cells (SMCs), osteoblasts and glycoproteins. Immunostaining confirmed that OMD was abundantly present in calcified plaques, localised to extracellular matrix and regions rich in α-SMA+ cells. In vivo, OMD was enriched in SMCs around calcified nodules in aortic media of nephrectomised rats and in plaques from ApoE-/- mice on warfarin. In vitro experiments revealed that OMD mRNA was upregulated in SMCs stimulated with IFNγ, BMP2, TGFβ1, phosphate and β-glycerophosphate, and by administration of recombinant human OMD protein (rhOMD). Mechanistically, addition of rhOMD repressed the calcification process of SMCs treated with phosphate by maintaining their contractile phenotype along with enriched matrix organisation, thereby attenuating SMC osteoblastic transformation. Mechanistically, the role of OMD is exerted likely through its link with SMAD3 and TGFB1 signalling, and interplay with BMP2 in vascular tissues.CONCLUSION: We report a consistent association of both circulating and tissue OMD levels with cardiovascular calcification, highlighting the potential of OMD as a clinical biomarker. OMD was localised in medial and intimal α-SMA+ regions of calcified cardiovascular tissues, induced by pro-inflammatory and pro-osteogenic stimuli, while the presence of OMD in extracellular environment attenuated SMC calcification.
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