JAG1-NOTCH4 Mechanosensing Drives Atherosclerosis

Souilhol, Céline; Li, Xiuying; Canham, Lindsay; Roddie, Hannah; Pirri, Daniela; Ayllón, Blanca Tardajos; Chambers, Emily; Dunning, Mark J.; Ariaans, Mark; Jin, Li; Fang, Yun; Fragiadaki, Maria; Ridger, Victoria; Serbanovic-Canic, Jovana; Val, Sarah De; Francis, Sheila; Chico, Timothy J. A.; Evans, Paul C.

doi:10.1101/2020.05.15.097931

Cited by 6 publications

(6 citation statements)

References 55 publications

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“…Cardiovascular development is a complex and tightly regulated process, highly conserved among vertebrates. Many of the conserved developmental pathways regulating cardiovascular development, including BMP, TGFβ, Notch and Wnt, are re-activated in arteries in adults and play critical roles in the development of cardiovascular diseases, including atherosclerosis 98 . Thus using zebrafish embryos and larvae not only as a vertebrate developmental model, but as a model for processes involved in human diseases, may provide important insights into molecular mechanisms regulating vascular disease (Figure 5).…”

Section: Vascular Disease Models Endothelial Dysfunction and Atheroscmentioning

confidence: 99%

Zebrafish as a tractable model of human cardiovascular disease

Bowley

Kugler

Wilkinson

et al. 2021

British J Pharmacology

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Mammalian models including non-human primates, pigs and rodents have been used extensively to study the mechanisms of cardiovascular disease. However, there is an increasing desire for alternative model systems that provide excellent scientific value while replacing or reducing the use of mammals. Here we review the use of zebrafish, Danio rerio, to study cardiovascular development and disease. The anatomy and physiology of zebrafish and mammalian cardiovascular systems are compared, and we describe the use of zebrafish models in studying the mechanisms of cardiac (e.g. congenital heart defects, cardiomyopathy, conduction disorders, regeneration) and vascular (endothelial dysfunction and atherosclerosis, lipid metabolism, vascular ageing, neurovascular physiology and stroke) pathologies. We also review the use of zebrafish for studying pharmacological responses to cardiovascular drugs, and describe several features of zebrafish that make them a compelling model for in vivo screening of compounds for the treatment cardiovascular disease.

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Section: Vascular Disease Models Endothelial Dysfunction and Atheroscmentioning

confidence: 99%

Zebrafish as a tractable model of human cardiovascular disease

Bowley

Kugler

Wilkinson

et al. 2021

British J Pharmacology

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“…In vitro models with simplified mechanical characteristics or reduced tissue complexity, ex vivo microfluidic channels, and cellular strain platforms have all been used to study the mechanosensitivity of Notch in vascular cells. 4,[56][57][58][59] The complexity of these systems should be gradually increased to more closely mimic the physiological environment.…”

Section: In Vitro Microphysiological Systemsmentioning

confidence: 99%

Ex VivoModels to Decipher the Molecular Mechanisms of Genetic Notch Cardiovascular Disorders

Ristori

Sjöqvist

Sahlgren

2021

Tissue Engineering Part C: Methods

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Notch is an evolutionary, conserved, cell-cell signaling pathway that is central to several biological processes, from tissue morphogenesis to homeostasis. It is therefore not surprising that several genetic mutations of Notch components cause inherited human diseases, especially cardiovascular disorders. Despite numerous efforts, current in vivo models are still insufficient to unravel the underlying mechanisms of these pathologies, hindering the development of utmost needed medical therapies. In this perspective review, we discuss the limitations of current murine models and outline how the combination of microphysiological systems (MPSs) and targeted computational models can lead to breakthroughs in this field. In particular, while MPSs enable the experimentation on human cells in controlled and physiological environments, in silico models can provide a versatile tool to translate the in vitro findings to the more complex in vivo setting. As a showcase example, we focus on Notch-related cardiovascular diseases, such as Alagille syndrome, Adams-Oliver syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

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“…The lesions prefer to localize within characteristic vessel geometries, such as the inside of the vessel curvature, downstream of stenosis, on the sidewall of a vessel bifurcation, and adjacent to the opening of a branch, which is the regions of low shear stress (LSS) and disturbed flow 14 . In addition, LSS impairs endothelial cells' function through a variety of signaling pathways 15,16 . The biomechanical damage effect of blood flow shear stress has attracted increasing attention 17 .…”

Section: Introductionmentioning

confidence: 99%

Lower shear stress exacerbates atherosclerosis by inducing the generation of neutrophil extracellular trapsviaPiezo1-mediated mechanosensation

Zhu

Wang

Chen

et al. 2023

Preprint

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Background: Atherosclerosis is a chronic lipid-driven inflammatory disease, largely influenced by hemodynamics. Neutrophil extracellular traps (NETs)-mediated inflammation plays an important role in atherosclerosis. However, little is known about the mechanism of the generation of NETs under different shear stress and subsequent damage to endothelial cells. We sought to identify a novel mechanical signal provokes NETs generation and to investigate its potential role in atherosclerosis. Methods: ApoE−/−mice were fed with high-fat diet (HFD) to induce atherosclerosis. The model of lower shear stress (LSS) with a partial ligation of the left carotid artery was established to assess the role of LSS in NETs generation and atherosclerotic lesions development. Furthermore, the underlying mechanism of LSS promoting NETs generation and injuring endothelial cells was deciphered in neutrophil-like human promyelocytic leukemia (HL-60) cells in parallel-plate flow chamber. Results: We found that LSS correlated spatially with both NETs and atherosclerosis, while inhibition of NETosis could significantly reduce plaque formation in ApoE−/−mice. In vitro, LSS could promote NETs generation directly through down-regulation of Piezo1, a mechanosensitive ion channel. downexpression of Piezol could activate neutrophils and promote NETosis in static. Conversely, Yoda1-evoked activation of Piezo1 attenuated LSS-induced NETosis. Mechanistically, the downexpression of Piezo1 resulted in decreased Ca2+ influx and increased histone deacetylase 2 (HDAC2), which increase reactive oxygen species levels, then led to NETosis. LSS-induced NETs generation promoted the apoptosis and adherence of endothelial cells. Conclusions: LSS directly promotes NETosis through piezo1-HDAC2 axis in atherosclerosis progression. This study uncovers the essential role of Piezo1-mediated mechanical signaling in NETs generation and plaque formation, which provides a promising therapeutic strategy for atherosclerosis.

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JAG1-NOTCH4 Mechanosensing Drives Atherosclerosis

Cited by 6 publications

References 55 publications

Zebrafish as a tractable model of human cardiovascular disease

Zebrafish as a tractable model of human cardiovascular disease

Ex VivoModels to Decipher the Molecular Mechanisms of Genetic Notch Cardiovascular Disorders

Lower shear stress exacerbates atherosclerosis by inducing the generation of neutrophil extracellular trapsviaPiezo1-mediated mechanosensation

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