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Published on: April 29, 2021
Zebrafish Model for Functional Screening of Flow-Responsive Genes.
Jovana Serbanovic-Canic1, Amalia de Luca1, Christina Warboys1
1From the Department of Infection, Immunity and Cardiovascular Disease (J.S.-C., L.A.L., S.H., I.G., M.M., S.F., C.S., N.B., J.-P.A., V.R., T.J.A.C., P.C.E.), INSIGNEO Institute for In Silico Medicine (J.S.-C., V.R., T.J.A.C., P.C.E.), and the Bateson Centre (J.S.-C., J.-P.A., T.J.A.C., P.C.E.), University of Sheffield, United Kingdom; and Departments of Cardiovascular Science (A.d.L., C.W., J.C.M., D.O.H.), Imaging (P.F.F., D.F.), Bioengineering (R.K.), and Aeronautics (S.S.) Imperial College London, United Kingdom; and Cancer Institute, Faculty of Medical Sciences (H.W.), University College London, United Kingdom.
Atherosclerosis research uses zebrafish to screen genes regulating endothelial cell apoptosis under disturbed blood flow. This functional screening identifies potential therapeutic targets for preventing vascular disease.
Area of Science:
- Cardiovascular Biology
- Mechanobiology
- Vascular Biology
Background:
- Atherosclerosis originates at arterial sites with disturbed blood flow and low shear stress.
- This mechanical environment induces endothelial cell (EC) apoptosis and dysfunction through incompletely understood mechanisms.
- Many shear-responsive genes identified via transcriptomics have unknown functions.
Purpose of the Study:
- To investigate the utility of zebrafish embryos for functional screening of mechanosensitive genes.
- To identify genes regulating EC apoptosis in response to mechanical forces in arteries.
- To explore potential therapeutic targets for endothelial injury at atheroprone sites.
Main Methods:
- Zebrafish embryos were used to model flow manipulation and EC apoptosis.
- Transcriptome profiling of ECs from porcine aorta identified candidate shear-responsive genes.
- Candidate genes were screened using a knockdown approach in zebrafish vasculature under varying flow conditions.
Main Results:
- Suppression of blood flow in zebrafish embryos increased EC apoptosis by approximately 10%.
- Four genes showed phenotypic changes: PERP and PDCD2L positively regulated apoptosis, while ANGPTL4 and CDH13 negatively regulated it.
- Regulation of perp, cdh13, angptl4, and pdcd2l by shear stress was confirmed in cultured ECs.
Conclusions:
- A zebrafish model combining flow manipulation and gene knockdown is effective for functional screening of mechanosensitive genes.
- This approach successfully identified key regulators of EC apoptosis in response to shear stress.
- The identified genes represent potential therapeutic targets for preventing or treating endothelial injury in atherosclerosis.
