From Lipid Retention to Immune-Mediate Inflammation and Associated Angiogenesis in the Pathogenesis of Atherosclerosis

Usman, Ammara; Ribatti, Doménico; Sadat, Umar; Gillard, Jonathan H.

doi:10.5551/jat.30460

Cited by 36 publications

(31 citation statements)

References 98 publications

(74 reference statements)

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“…Activation of immune signalling in EC is associated with deviant angiogenesis complicating various diseases, and yet the mechanisms remain unclear (Thebaud & Abman, ; Usman et al . ). In this study, we reveal the mechanisms by which bacteria can directly programme EC phenotypic changes that contribute to sepsis‐induced inflammatory angiogenesis.…”

Section: Discussionmentioning

confidence: 97%

“…The ramifications of EC‐centric TLR‐ERK‐FOXC2‐DLL4‐activation for human diseases such as rheumatoid arthritis and atherosclerosis characterized by abnormal inflammatory angiogenesis are points of broader interest to the research community (Usman et al . ; Tas et al . ).…”

Section: Discussionmentioning

confidence: 99%

“…This is of translational significance as sepsis and inflammation programme deviant blood vessel formation observed in human diseases such as bronchopulmonary dysplasia (BPD) in premature babies, and rheumatoid arthritis and atherosclerosis in adults, the mechanistic origins of which remain unclear (Thebaud & Abman, ; Usman et al . ; Tas et al . ).…”

Section: Introductionmentioning

confidence: 99%

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Endothelial immune activation programmes cell‐fate decisions and angiogenesis by inducing angiogenesis regulator DLL4 through TLR4‐ERK‐FOXC2 signalling

Sheng

Menden

Korfhagen

et al. 2018

The Journal of Physiology

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Endothelial cells (ECs) mediate a specific and robust immune response to bacteria in sepsis through the activation of toll-like receptor (TLR) signalling. The mechanisms by which bacterial ligands released during sepsis programme EC specification and altered angiogenesis remain unclear. We postulated that the forkhead box protein C2 (FOXC2) transcriptional factor directs EC cell-fate decisions and angiogenesis during TLR signalling. In human lung ECs, lipopolysaccharide (LPS) induced ERK phosphorylation, FOXC2, and delta-like 4 (DLL4, the master regulator of sprouting angiogenesis expression) in a TLR4-dependent manner. LPS-mediated ERK phosphorylation resulted in FOXC2-ERK protein ligation, ERK-dependent FOXC2 serine and threonine phosphorylation, and subsequent activation of DLL4 gene expression. Chemical inhibition of ERK or ERK-2 dominant negative transfection disrupted LPS-mediated FOXC2 phosphorylation and transcriptional activation of FOXC2. FOXC2-siRNA or ERK-inhibition attenuated LPS-induced DLL4 expression and angiogenic sprouting in vitro. In vivo, intraperitoneal LPS induced ERK and FOXC2 phosphorylation, FOXC2 binding to DLL4 promoter, and FOXC2/DLL4 expression in the lung. ERK-inhibition suppressed LPS-induced FOXC2 phosphorylation, FOXC2-DLL4 promoter binding, and induction of FOXC2 and DLL4 in mouse lung ECs. LPS induced aberrant retinal angiogenesis and DLL4 expression in neonatal mice, which was attenuated with ERK inhibition. FOXC2 mice treated with LPS showed a mitigated increase in FOXC2 and DLL4 compared to FOXC2 mice. These data reveal a new mechanism (TLR4-ERK-FOXC2-DLL4) by which sepsis-induced EC TLR signalling programmes EC specification and altered angiogenesis.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endothelial immune activation programmes cell‐fate decisions and angiogenesis by inducing angiogenesis regulator DLL4 through TLR4‐ERK‐FOXC2 signalling

Sheng

Menden

Korfhagen

et al. 2018

The Journal of Physiology

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“…Extensive studies over the past decade have provided substantial evidence that the extent of inflammation and angiogenesis within a plaque are directly linked to its risk of rupture (5,6). Among inflammatory cells within the plaque, macrophages appear to play a major role.…”

mentioning

confidence: 99%

Dual-Modality Activity-Based Probes as Molecular Imaging Agents for Vascular Inflammation

Withana

Saito

et al. 2016

J Nucl Med

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Macrophages are cellular mediators of vascular inflammation and are involved in the formation of atherosclerotic plaques. These immune cells secrete proteases such as matrix metalloproteinases and cathepsins that contribute to disease formation and progression. Here, we demonstrate that activity-based probes (ABPs) targeting cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes can also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations. Methods: Macrophage-rich carotid lesions were induced in FVB mice fed on a high-fat diet by streptozotocin injection followed by ligation of the left common carotid artery. Mice with carotid atherosclerotic plaques were injected with the optical or dual-modality probes BMV109 and BMV101, respectively, via the tail vein and noninvasively imaged by optical and small-animal PET/CT at different time points. After noninvasive imaging, the murine carotid arteries were imaged in situ and ex vivo, followed by immunofluorescence staining to confirm target labeling. Additionally, human carotid plaques were topically labeled with the probe and analyzed by both sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunofluorescence staining to confirm the primary targets of the probe. Results: Quantitative analysis of the signal intensity from both optical and PET/CT imaging showed significantly higher levels of accumulation of BMV109 and BMV101 (P , 0.005 and P , 0.05, respectively) in the ligated left carotid arteries than the right carotid or healthy arteries. Immunofluorescence staining for macrophages in cross-sectional slices of the murine artery demonstrated substantial infiltration of macrophages in the neointima and adventitia of the ligated left carotid arteries compared with the right. Analysis of the human plaque tissues by sodium dodecyl sulfate polyacrylamide gel electrophoresis confirmed that the primary targets of the probe were cathepsins X, B, S, and L. Immunofluorescence labeling of the human tissue with the probe demonstrated colocalization of the probe with CD68, elastin, and cathepsin S, similar to that observed in the experimental carotid inflammation murine model. Conclusion: We demonstrate that ABPs targeting the cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes could also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations. Therefore, ABPs targeting the cysteine cathepsins are potentially valuable new reagents for rapid and noninvasive imaging of atherosclerotic disease progression and plaque vulnerability.

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“…In segments with AIT/PIT morphology, increased necrotic core burden appeared to be associated with plaque progression. This finding is supported by cumulative evidence which underscore the role of lipid tissue on the initiation of vulnerable plaque formation through metabolic pathways that promote low-density lipoprotein entrapment, smooth muscle cells proliferation and activation of vascular inflammation 17. In FT and FCa plaques, the segments that exhibited disease progression had increased fibrotic tissue component, numerically lower calcific burden and increased incidence of neovessels.…”

Section: Resultsmentioning

confidence: 63%

Implications of the local haemodynamic forces on the phenotype of coronary plaques

Bourantas

Zanchin

Sakellarios

et al. 2019

Heart

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AimTo examine the effect of endothelial shear stress (ESS) on the dynamic changes in plaque phenotype.MethodsPatients with myocardial infarction that had intravascular ultrasound-virtual histology (IVUS-VH) and optical coherence tomography (OCT) at baseline and 13-month follow-up were studied. The IVUS-VH data were used to reconstruct the nonculprit vessels, and in the obtained models the ESS was estimated in 3 mm segments. Plaque morphology was derived in each segment from IVUS-VH and OCT. Disease progression was defined as the presence of ≥2 out of the following criteria: reduction in lumen area, increase in plaque burden and change of plaque morphology to a more vulnerable phenotype. Linear mixed effects models were used to assess the effect of ESS in different phenotypes.ResultsSixty-eight vessels were included in the analysis. Low ESS was associated with plaque progression in all phenotypes. The effect of ESS on plaque burden (p for interaction=0.467) and phenotype (p for interaction=0.188) was similar in all plaque types, whereas the effect of ESS on the changes in lumen dimensions was more prominent in disease-free (β=0.70, p<0.001) than fibrotic/fibrocalcific (β=0.28, p<0.001) or lipid-rich plaques (β=0.15, p=0.015). Standalone IVUS-VH misclassified plaque morphology in one-third of the cases leading to erroneous estimations about the effect of ESS on plaque evolution in different phenotypes.ConclusionsThe effect of ESS on plaque progression is similar in all phenotypes and cannot be accurately assessed by standalone IVUS-VH which often misclassifies plaque morphology. Therefore, multimodality imaging should be considered to examine the implications of ESS on plaque evolution.Clinical trial registrationNCT00962416; Post-results.

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From Lipid Retention to Immune-Mediate Inflammation and Associated Angiogenesis in the Pathogenesis of Atherosclerosis

Cited by 36 publications

References 98 publications

Endothelial immune activation programmes cell‐fate decisions and angiogenesis by inducing angiogenesis regulator DLL4 through TLR4‐ERK‐FOXC2 signalling

Endothelial immune activation programmes cell‐fate decisions and angiogenesis by inducing angiogenesis regulator DLL4 through TLR4‐ERK‐FOXC2 signalling

Dual-Modality Activity-Based Probes as Molecular Imaging Agents for Vascular Inflammation

Implications of the local haemodynamic forces on the phenotype of coronary plaques

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