PUBLICATION
flt1 inactivation promotes zebrafish cardiac regeneration by enhancing endothelial activity and limiting the fibrotic response
- Authors
- Wang, Z.Y., Mehra, A., Wang, Q.C., Gupta, S., Ribeiro da Silva, A., Juan, T., Günther, S., Looso, M., Detleffsen, J., Stainier, D.Y.R., Marín-Juez, R.
- ID
- ZDB-PUB-241130-3
- Date
- 2024
- Source
- Development (Cambridge, England) 151(23): (Journal)
- Registered Authors
- Juan, Thomas, Marín-Juez, Rubén, Stainier, Didier
- Keywords
- Cardiac regeneration, Egr3, Flt1, Vegfa, Zebrafish
- Datasets
- GEO:GSE264406
- MeSH Terms
-
- Signal Transduction/genetics
- Cell Differentiation*/genetics
- Heart*
- Vascular Endothelial Growth Factor A*/genetics
- Vascular Endothelial Growth Factor A*/metabolism
- Early Growth Response Protein 3/genetics
- Early Growth Response Protein 3/metabolism
- Zebrafish*
- Fibrosis
- Regeneration*/genetics
- Myocytes, Cardiac*/metabolism
- Cell Proliferation/genetics
- Animals
- Neovascularization, Physiologic/genetics
- Endocardium/metabolism
- Endocardium/pathology
- Vascular Endothelial Growth Factor Receptor-1*/genetics
- Vascular Endothelial Growth Factor Receptor-1*/metabolism
- Myofibroblasts/metabolism
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 39612288 Full text @ Development
Citation
Wang, Z.Y., Mehra, A., Wang, Q.C., Gupta, S., Ribeiro da Silva, A., Juan, T., Günther, S., Looso, M., Detleffsen, J., Stainier, D.Y.R., Marín-Juez, R. (2024) flt1 inactivation promotes zebrafish cardiac regeneration by enhancing endothelial activity and limiting the fibrotic response. Development (Cambridge, England). 151(23):.
Abstract
VEGFA administration has been explored as a pro-angiogenic therapy for cardiovascular diseases including heart failure for several years, but with little success. Here, we investigate a different approach to augment VEGFA bioavailability: by deleting the VEGFA decoy receptor VEGFR1 (also known as FLT1), one can achieve more physiological VEGFA concentrations. We find that after cryoinjury, zebrafish flt1 mutant hearts display enhanced coronary revascularization and endocardial expansion, increased cardiomyocyte dedifferentiation and proliferation, and decreased scarring. Suppressing Vegfa signaling in flt1 mutants abrogates these beneficial effects of flt1 deletion. Transcriptomic analyses of cryoinjured flt1 mutant hearts reveal enhanced endothelial MAPK/ERK signaling and downregulation of the transcription factor gene egr3. Using newly generated genetic tools, we observe egr3 upregulation in the regenerating endocardium, and find that Egr3 promotes myofibroblast differentiation. These data indicate that with enhanced Vegfa bioavailability, the endocardium limits myofibroblast differentiation via egr3 downregulation, thereby providing a more permissive microenvironment for cardiomyocyte replenishment after injury.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping