Promoter Usage and Dynamics in Vascular Smooth Muscle Cells Exposed to Fibroblast Growth Factor-2 or Interleukin-1β

Alhendi, Ahmad M. N.; Patrikakis, Margaret; Daub, Carsten O.; Kawaji, Hideya; Itoh, Masayoshi; Hoon, Michiel de; Carninci, Piero; Hayashizaki, Yoshihide; Arner, Peter; Khachigian, Levon M.

doi:10.1038/s41598-018-30702-4

Cited by 10 publications

(6 citation statements)

References 50 publications

(68 reference statements)

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“…The increased activation of matrix metalloproteinases in pathologically altered human cardiac valves emphasizes the crucial role of the extracellular matrix in the development of this disease [26]. Similar mechanisms are held responsible for rupture of atherosclerotic plaques [21].…”

Section: Discussionmentioning

confidence: 99%

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Evidence of woven bone formation in carotid artery plaques

Mirzaie¹,

Guliyev²,

Schultz³

et al. 2021

J Cardiol Cardiovasc Med

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Objective: Plaque morphology plays an important prognostic role in the occurrence of cerebrovascular events. Echolucent and heterogeneous plaques, in particular, carry an increased risk of subsequent stroke. Depending on the quality of the plaque echogenicity based on B-mode ultrasound examination, carotid plaques divide into a soft lipid-rich plaque and a hard plaque with calcification. The aim of this study was to investigate structural changes in the basement membrane of different carotid artery plaque types. Patients and methods: Biopsies were taken from 10 male patients (average age; 75 + 1 years) and 7 females (68 + 3 years). The study population included patients suffering from a filiform stenosis of the carotid artery, 8 patients with acute cerebrovascular events and 9 with asymptomatic stenosis. Scanning electron and polarised light microscopic investigations were carried out on explanted plaques to determine the morphology of calcified areas in vascular lesions. Results: By means of scanning electron microscopy, multiple foci of local calcification were identified. The endothelial layer was partially desquamated from the basement membrane and showed island-like formations. Polarised light microscopy allows us to distinguish between soft plaques with transparent structure and hard plaques with woven bone formation. Conclusion: The major finding of our study is the presence of woven bone tissue in hard plaques of carotid arteries, which may result from pathological strains or mechanical overloading of the collagen fibers. These data suggest a certain parallel with sclerosis of human aortic valves due to their similar morphological characteristics.

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Section: Discussionmentioning

confidence: 99%

“…Mechanisms of plaque rupture have been extensively studied and several parameters have been found to interact: extracellular matrix, in lammatory cells, gelatinases, stromelysins, matrilysin and MMp expression induced by oxidised lipids etc. [17][18][19][20][21][22].…”

Section: Discussionmentioning

confidence: 99%

Evidence of woven bone formation in carotid artery plaques

Mirzaie¹,

Guliyev²,

Schultz³

et al. 2021

J Cardiol Cardiovasc Med

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“…Knockdown studies have demonstrated a key role for Egr‐1 in cell migration. 30 , 31 To determine the importance of Ser26 in endothelial migration, we used a dual‐chamber model in which cells traveled from the upper chamber toward VEGF‐A 165 as a chemoattractant in the lower chamber. There was a 1.9‐fold increase in the number of wild‐type cells migrating toward VEGF‐A 165 .…”

Section: Resultsmentioning

confidence: 99%

Serine 26 in Early Growth Response‐1 Is Critical for Endothelial Proliferation, Migration, and Network Formation

Santiago

Khachigian

2021

JAHA

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Background Vascular endothelial cell proliferation, migration, and network formation are key proangiogenic processes involving the prototypic immediate early gene product, Egr‐1 (early growth response‐1). Egr‐1 undergoes phosphorylation at a conserved Ser26 but its function is completely unknown in endothelial cells or any other cell type. Methods and Results A CRISPR/Cas9 strategy was used to introduce a homozygous Ser26>Ala mutation into endogenous Egr‐1 in human microvascular endothelial cells. In the course of generating mutant cells, we produced cells with homozygous deletion in Egr ‐1 caused by frameshift and premature termination. We found that Ser26 mutation in Egr‐1, or Egr‐1 deletion, perturbed endothelial cell proliferation in models of cell counting or real‐time growth using the xCELLigence System. We found that Ser26 mutation or Egr‐1 deletion ameliorated endothelial cell migration toward VEGF‐A 165 (vascular endothelial growth factor‐A) in a dual‐chamber model. On solubilized basement membrane preparations, Ser26 mutation or Egr‐1 deletion prevented endothelial network (or tubule) formation, an in vitro model of angiogenesis. Flow cytometry further revealed that Ser26 mutation or Egr‐1 deletion elevated early and late apoptosis. Finally, we demonstrated that Ser26 mutation or Egr‐1 deletion increased VE‐cadherin (vascular endothelial cadherin) expression, a regulator of endothelial adhesion and signaling, permeability, and angiogenesis. Conclusions These findings not only indicate that Egr‐1 is essential for endothelial cell proliferation, migration, and network formation, but also show that point mutation in Ser26 is sufficient to impair each of these processes and trigger apoptosis as effectively as the absence of Egr‐1. This highlights the importance of Ser26 in Egr‐1 for a range of proangiogenic processes.

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“…Among the top ten hub genes identified (IL4, FOS, PTPRC, CCL4, TGFB1, CD69, EGR1, IL1R1, CD83, and HMOX1), FOS was involved in the TNF-α signaling pathway and was significantly upregulated in CTEPH VSMCs. FOS, considered an immediate early gene because of its transient and rapid change in expression in response to stimuli, participates broadly in the regulation of cell proliferation and migration ( Chen et al, 2016 ; van et al, 2017 ; Alhendi et al, 2018 ). FOS upregulation is observed in some cardiovascular diseases, including viral myocarditis, acute myocardial infarction, heart failure, and abdominal aortic aneurysms ( Zhang et al, 2013 ; Zhao et al, 2019 ), indicating a potential link between FOS and these pathophysiologic processes.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Gene Correlated With Vascular Smooth Muscle Cells Proliferation and Migration in Chronic Thromboembolic Pulmonary Hypertension

Wang

Sun

et al. 2021

Front. Physiol.

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Objective: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of the proximal pulmonary arteries, which result in vascular remodeling of the distal pulmonary artery. While the cellular and molecular mechanisms underlying CTEPH pathogenesis remain incompletely understood, recent evidence implicates vascular remodeling. Here, we identify the molecular mechanisms that contribute to vascular remodeling in CTEPH.Methods: Microarray data (GSE130391) for patients with CTEPH and healthy controls were downloaded from the Gene Expression Omnibus (GEO) and screened for differentially expressed genes (DEGs). DEGs were functionally annotated using Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. A protein–protein interaction (PPI) network was constructed to identify hub genes. Finally, pulmonary artery samples were harvested from patients with CTEPH (n = 10) and from controls (n = 10) and primary vascular smooth muscle cells (VSMCs) were cultured. Effects of the proto-oncogene FOS on VSMC proliferation and migration were assessed using expression and knockdown studies.Results: We detected a total of 292 DEGs, including 151 upregulated and 141 downregulated genes. GO analysis revealed enrichment of DEGs in biological processes of signal transduction, response to lipopolysaccharide, signal transduction, and myeloid dendritic cell differentiation. Molecular function analysis revealed enrichment in tumor necrosis factor (TNF)-activated receptor activity, transcriptional activator activity, and protein homodimerization activity. The expression of TNF-α and its receptor (sTNFR1 and sTNFR2) were significantly higher in CTEPH group, compared with control group. KEGG pathway analysis revealed enrichment in salmonella infection, pathways in cancer, osteoclast differentiation, and cytokine-cytokine receptor interaction. Hub genes in the PPI included FOS, suggesting an important role for this gene in vascular remodeling in CTEPH. Primary VSMCs derived from patients with CTEPH showed increased FOS expression and high proliferation and migration, which was attenuated by FOS inhibition. In control VSMCs, TNF-α treatment increased proliferation and migration, which FOS inhibition likewise attenuated.Conclusion: TNF-α drives CTEPH pathogenesis by promoting VSMC proliferation and migration via increased FOS expression. These results advance our understanding of the molecular mechanisms of vascular remodeling in CTEPH, and may inform the development of new therapeutic targets.

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Promoter Usage and Dynamics in Vascular Smooth Muscle Cells Exposed to Fibroblast Growth Factor-2 or Interleukin-1β

Cited by 10 publications

References 50 publications

Evidence of woven bone formation in carotid artery plaques

Evidence of woven bone formation in carotid artery plaques

Serine 26 in Early Growth Response‐1 Is Critical for Endothelial Proliferation, Migration, and Network Formation

Identification of a Novel Gene Correlated With Vascular Smooth Muscle Cells Proliferation and Migration in Chronic Thromboembolic Pulmonary Hypertension

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