Zebrafish Model for Functional Screening of Flow-Responsive Genes

Serbanovic-Canic, Jovana; Luca, Amalia De; Warboys, Christina M.; Ferreira, Pedro F.; Luong, La; Hsiao, Sarah; Gauci, Ismael; Mahmoud, Marwa; Feng, Shuang; Souilhol, Céline; Bowden, Neil; Ashton, J.P.; Walczak, Henning; Firmin, David N.; Krams, R.; Mason, Justin C.; Haskard, D. O.; Sherwin, Spencer J.; Ridger, Victoria; Chico, Timothy J. A.; Evans, Paul C.

doi:10.1161/atvbaha.116.308502

Cited by 46 publications

(60 citation statements)

References 50 publications

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“…Our work complements previous work (Serbanovic-Canic et al, 2017) which found blood flow cessation to induce EC apoptosis in zebrafish embryos at 30hpf, while our assessment of cerebral microglia numbers extends the examinations of Xu et al who limited their studies to microglia of the tectum (Xu et al, 2016). Our finding that NO is lacking in the bulbus arteriosus at 3dpf in fish without blood flow is the first functional evidence of bulbus arteriosus NO to be blood flow dependent (Grimes et al, 2006).…”

Section: Discussionsupporting

confidence: 88%

“…Additionally, control morpholino group account for injection-induced developmental delays (Stainier et al, 2017). Previous studies used this method to study the impact of blood flow on specific cerebral (Fortuna et al, 2015;Rödel Claudia Jasmin et al, 2019) and trunk vessels (Watson et al, 2013), showing reduced trunk EC numbers when blood flow is absent (Serbanovic-Canic et al, 2017;Watson et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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The effect of absent blood flow on the zebrafish cerebral and trunk vasculature

Kugler

Snodgrass

Bowley

et al. 2020

Preprint

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The role of blood flow is complex and context-dependent. In this study, we quantify the effect of the lack of blood flow on vascular development and compare its impact in two vascular beds, namely the cerebral and trunk vasculature, using zebrafish as preclinical model. We performed this by analysing vascular topology, endothelial cell number, apoptosis, and inflammatory response in animals with normal blood flow or absent blood flow. We find that absent blood flow reduced vascular area and endothelial cell number significantly in both examined vascular beds, but the effect is more severe in the cerebral vasculature. Similarly, while stereotypic vascular patterning in the trunk is maintained, intra-cerebral vessels show altered patterning. Absent blood flow lead to an increase in non-EC-specific apoptosis without increasing tissue inflammation, as quantified by cerebral immune cell numbers and nitric oxide. In conclusion, blood flow is essential for cellular survival in both the trunk and cerebral vasculature, but particularly intra-cerebral vessels are affected by the lack of blood flow, suggesting that responses to blood flow differ between these two vascular beds.Key pointsWe here use zebrafish as a model to quantitatively assess the impact of the lack of blood flow in development and compare its impact in two vascular beds, namely the cerebral to trunk vasculature.In both vascular beds, vascular growth and endothelial cell number are reduced by lack of blood flow, with increasing effect size from 2-5 days post fertilisation.Examination of vascular patterning shows that while stereotypic patterning in the trunk is preserved, the intra-cerebral vasculature patterning is altered.We found non-EC-specific cell death to be increased in both vascular beds, with a larger effect size in the brain, but that this cell death occurs without triggering tissue inflammation.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

The effect of absent blood flow on the zebrafish cerebral and trunk vasculature

Kugler

Snodgrass

Bowley

et al. 2020

Preprint

Self Cite

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“…These data suggest that the Wnt pathway may be regulated by mechanical forces, although they may also be increased secondary to other mechanically activated pathways. Interestingly, the expression of Lrp6 is increased in cells exposed to uniform flow (65) suggesting that different Wnt pathways may be active under different flow conditions. Nuclear accumulation of β-catenin has also been observed in an atheroprone region of the mouse aorta, in the absence of lesions, suggesting flow-dependent regulation.…”

Section: Mechanical Regulation Of Wnt Signalling In the Vasculaturementioning

confidence: 99%

Mechanoactivation of Wnt/β-catenin pathways in health and disease

Warboys

2018

Emerging Topics in Life Sciences

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Mechanical forces play an important role in regulating tissue development and homeostasis in multiple cell types including bone, joint, epithelial and vascular cells, and are also implicated in the development of diseases, e.g. osteoporosis, cardiovascular disease and osteoarthritis. Defining the mechanisms by which cells sense and respond to mechanical forces therefore has important implications for our understanding of tissue function in health and disease and may lead to the identification of targets for therapeutic intervention. Mechanoactivation of the Wnt signalling pathway was first identified in osteoblasts with a key role for β-catenin demonstrated in loading-induced osteogenesis. Since then, mechanoregulation of the Wnt pathway has also been observed in stem cells, epithelium, chondrocytes and vascular and lymphatic endothelium. Wnt can signal through both canonical and non-canonical pathways, and evidence suggests that both can mediate responses to mechanical strain, stretch and shear stress. This review will discuss our current understanding of the activation of the Wnt pathway in response to mechanical forces.

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“…Given the different effects of Jag1 and Dll4 on atherosclerosis, we hypothesised that Notch receptors and ligands may have a different spatial pattern of expression in arteries. This was tested by qRT-PCR analysis of transcripts of Notch receptors and their ligands isolated from regions of the porcine aorta exposed to LOSS (inner curvature) or HSS (outer curvature) using a shear stress map generated previously by our group 16 . The expression of JAG1 and NOTCH4 mRNA was significantly enhanced at sites of LOSS compared to HSS whereas the expression of DLL4, NOTCH1, NOTCH2 and NOTCH3 was similar between these sites ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Data are presented as means values ± SEM. Statistical analysis were performed with 16 . Based on this map, endothelial cells were specifically isolated from LOSS area versus HSS area in the porcine aortic arch.…”

Section: Resultsmentioning

confidence: 99%

JAG1-NOTCH4 Mechanosensing Drives Atherosclerosis

Souilhol

Canham

et al. 2020

Preprint

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Endothelial cell (EC) sensing of fluid shear stress regulates atherosclerosis, a disease of arteries that causes heart attack and stroke. Atherosclerosis preferentially develops at regions of arteries exposed to low oscillatory shear stress (LOSS), whereas high shear regions are protected. We show using inducible EC-specific genetic deletion in hyperlipidaemic mice that the Notch ligands JAG1 and DLL4 have opposing roles in atherosclerosis. While endothelial Jag1 promoted atherosclerosis at sites of LOSS, endothelial Dll4 was atheroprotective. Analysis of porcine and murine arteries and cultured human coronary artery EC exposed to experimental flow revealed that JAG1 and its receptor NOTCH4 are strongly upregulated by LOSS. Functional studies in cultured cells and in mice with EC-specific deletion of Jag1 show that JAG1-NOTCH4 signalling drives vascular dysfunction by repressing endothelial repair. These data demonstrate a fundamental role for JAG1-NOTCH4 in sensing LOSS during disease, and suggest therapeutic targeting of this pathway to treat atherosclerosis.

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Zebrafish Model for Functional Screening of Flow-Responsive Genes

Abstract: Supplemental Digital Content is available in the text.

Cited by 46 publications

References 50 publications

The effect of absent blood flow on the zebrafish cerebral and trunk vasculature

The effect of absent blood flow on the zebrafish cerebral and trunk vasculature

Mechanoactivation of Wnt/β-catenin pathways in health and disease

JAG1-NOTCH4 Mechanosensing Drives Atherosclerosis

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