Human atherosclerotic plaque transcriptomics reveals endothelial beta-2 spectrin as a potential regulator a leaky plaque microvasculature phenotype
Angiogenesis, vol. 27, pp. 461–474
Abstract
The presence of atherosclerotic plaque vessels is a critical factor in plaque destabilization. This may be attributable to the leaky phenotype of these microvessels, although direct proof for this notion is lacking. In this study, we investigated molecular and cellular patterns of stable and hemorrhaged human plaque to identify novel drivers of intraplaque vessel dysfunction. From transcriptome data of a human atherosclerotic lesion cohort, we reconstructed a co-expression network, identifying a gene module strongly and selectively correlated with both plaque microvascular density and inflammation. Spectrin Beta Non-Erythrocytic 1 (sptbn1) was identified as one of the central hubs of this module (along with zeb1 and dock1) and was selected for further study based on its predominant endothelial expression. Silencing of sptbn1 enhanced leukocyte transmigration and vascular permeability in vitro, characterized by an increased number of focal adhesions and reduced junctional VE-cadherin. In vivo, sptbn1 knockdown in zebrafish impaired the development of the caudal vein plexus. Mechanistically, increased substrate stiffness was associated with sptbn1 downregulation in endothelial cells in vitro and in human vessels. Plaque SPTBN1 mRNA and protein expression were found to correlate with an enhanced presence of intraplaque hemorrhage and future cardiovascular disease (CVD) events during follow-up. In conclusion, we identify SPTBN1 as a central hub gene in a gene program correlating with plaque vascularisation. SPTBN1 was regulated by substrate stiffness in vitro while silencing blocked vascular development in vivo, and compromised barrier function in vitro. Together, SPTBN1 is identified as a new potential regulator of the leaky phenotype of atherosclerotic plaque microvessels.
Authors 22
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Sanquin · Maastricht University
Affiliation as printed
Department of Pathology, Experimental Vascular Pathology Group, Maastricht University, PO box 5800, 6202 AZ, Maastricht, The Netherlands
Department of Plasma Proteins, Laboratory for Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands
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Affiliation as printed
Department of Pathology, Experimental Vascular Pathology Group, Maastricht University, PO box 5800, 6202 AZ, Maastricht, The Netherlands
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Affiliation as printed
Department of Pathology, Experimental Vascular Pathology Group, Maastricht University, PO box 5800, 6202 AZ, Maastricht, The Netherlands
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Affiliation as printed
Laboratory of Protein Signaling and Interactions, GIGA, Liège Université, Liège, Belgium
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Karolinska University Hospital · Karolinska Institutet
Affiliation as printed
Division of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska Hospital, Stockholm, Sweden
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Affiliation as printed
Department of Pathology, Experimental Vascular Pathology Group, Maastricht University, PO box 5800, 6202 AZ, Maastricht, The Netherlands
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Affiliation as printed
Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany
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Affiliation as printed
Department of Pathology, Experimental Vascular Pathology Group, Maastricht University, PO box 5800, 6202 AZ, Maastricht, The Netherlands
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Affiliation as printed
Department of Plasma Proteins, Laboratory for Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands
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Affiliation as printed
Department of Pathology, Experimental Vascular Pathology Group, Maastricht University, PO box 5800, 6202 AZ, Maastricht, The Netherlands
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Vascular Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
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Affiliation as printed
Department of Pathology, Experimental Vascular Pathology Group, Maastricht University, PO box 5800, 6202 AZ, Maastricht, The Netherlands
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Affiliation as printed
Department of Pathology, Experimental Vascular Pathology Group, Maastricht University, PO box 5800, 6202 AZ, Maastricht, The Netherlands
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Amsterdam UMC Location University of Amsterdam
Affiliation as printed
Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Laboratory of Clinical Chemistry and Haematology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
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University of Münster · Maastricht University
Affiliation as printed
Department of Biochemistry, Maastricht University, Maastricht, The Netherlands
Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany
Maastricht Center for Systems Biology (MaCSBio, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
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Affiliation as printed
Department of Molecular Cell Biology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
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Karolinska University Hospital · Karolinska Institutet
Affiliation as printed
Division of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska Hospital, Stockholm, Sweden
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Affiliation as printed
Laboratory of Protein Signaling and Interactions, GIGA, Liège Université, Liège, Belgium
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Affiliation as printed
Department of Plasma Proteins, Laboratory for Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands
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Judith C. Sluimer Aachen Department for Renal and Hypertensive Rheumatological and Immunological Diseases (Medical Clinic II)
Maastricht University · RWTH Aachen University · University of Edinburgh
Affiliation as printed
Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
Department for Renal and Hypertensive, Rheumatological and Immunological Diseases (Medical Clinic II), RWTH Aachen, Aachen, Germany
Department of Pathology, Experimental Vascular Pathology Group, Maastricht University, PO box 5800, 6202 AZ, Maastricht, The Netherlands
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Maastricht University · RWTH Aachen University
Affiliation as printed
Department of Pathology, Experimental Vascular Pathology Group, Maastricht University, PO box 5800, 6202 AZ, Maastricht, The Netherlands. erik.biessen@mumc.nl
Institute for Molecular Cardiovascular Research, RWTH Aachen, Aachen, Germany. erik.biessen@mumc.nl
Institute for Molecular Cardiovascular Research, RWTH Aachen, Aachen, Germany
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