Imperial College London

ProfessorSpencerSherwin

Faculty of EngineeringDepartment of Aeronautics

Professor of Computational Fluid Mechanics
 
 
 
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Contact

 

+44 (0)20 7594 5052s.sherwin Website

 
 
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Location

 

313BCity and Guilds BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Serbanovic-Canic:2016:10.1161/ATVBAHA.116.308502,
author = {Serbanovic-Canic, J and de, Luca A and Warboys, C and Ferreira, PF and Luong, LA and Hsiao, S and Gauci, I and Mahmoud, M and Feng, S and Souilhol, C and Bowden, N and Ashton, JP and Walczak, H and Firmin, D and Krams, R and Mason, JC and Haskard, DO and Sherwin, S and Ridger, V and Chico, TJ and Evans, PC},
doi = {10.1161/ATVBAHA.116.308502},
journal = {Arteriosclerosis Thrombosis and Vascular Biology},
title = {Zebrafish model for functional screening of flow-responsive genes},
url = {http://dx.doi.org/10.1161/ATVBAHA.116.308502},
volume = {36},
year = {2016}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - OBJECTIVE: Atherosclerosis is initiated at branches and bends of arteries exposed to disturbed blood flow that generates low shear stress. This mechanical environment promotes lesions by inducing endothelial cell (EC) apoptosis and dysfunction via mechanisms that are incompletely understood. Although transcriptome-based studies have identified multiple shear-responsive genes, most of them have an unknown function. To address this, we investigated whether zebrafish embryos can be used for functional screening of mechanosensitive genes that regulate EC apoptosis in mammalian arteries. APPROACH AND RESULTS: First, we demonstrated that flow regulates EC apoptosis in developing zebrafish vasculature. Specifically, suppression of blood flow in zebrafish embryos (by targeting cardiac troponin) enhanced that rate of EC apoptosis (≈10%) compared with controls exposed to flow (≈1%). A panel of candidate regulators of apoptosis were identified by transcriptome profiling of ECs from high and low shear stress regions of the porcine aorta. Genes that displayed the greatest differential expression and possessed 1 to 2 zebrafish orthologues were screened for the regulation of apoptosis in zebrafish vasculature exposed to flow or no-flow conditions using a knockdown approach. A phenotypic change was observed in 4 genes; p53-related protein (PERP) and programmed cell death 2-like protein functioned as positive regulators of apoptosis, whereas angiopoietin-like 4 and cadherin 13 were negative regulators. The regulation of perp, cdh13, angptl4, and pdcd2l by shear stress and the effects of perp and cdh13 on EC apoptosis were confirmed by studies of cultured EC exposed to flow. CONCLUSIONS: We conclude that a zebrafish model of flow manipulation coupled to gene knockdown can be used for functional screening of mechanosensitive genes in vascular ECs, thus providing potential therapeutic targets to prevent or treat endothelial injury at atheroprone sites.
AU - Serbanovic-Canic,J
AU - de,Luca A
AU - Warboys,C
AU - Ferreira,PF
AU - Luong,LA
AU - Hsiao,S
AU - Gauci,I
AU - Mahmoud,M
AU - Feng,S
AU - Souilhol,C
AU - Bowden,N
AU - Ashton,JP
AU - Walczak,H
AU - Firmin,D
AU - Krams,R
AU - Mason,JC
AU - Haskard,DO
AU - Sherwin,S
AU - Ridger,V
AU - Chico,TJ
AU - Evans,PC
DO - 10.1161/ATVBAHA.116.308502
PY - 2016///
SN - 1524-4636
TI - Zebrafish model for functional screening of flow-responsive genes
T2 - Arteriosclerosis Thrombosis and Vascular Biology
UR - http://dx.doi.org/10.1161/ATVBAHA.116.308502
UR - http://www.ncbi.nlm.nih.gov/pubmed/27834691
UR - http://hdl.handle.net/10044/1/42976
VL - 36
ER -