flt1 inactivation promotes zebrafish cardiac regeneration by enhancing endothelial activity and limiting the fibrotic response.

Autor:	Wang ZY; Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.; German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany., Mehra A; Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.; German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany., Wang QC; Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.; German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany., Gupta S; Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.; German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany., Ribeiro da Silva A; Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.; German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany., Juan T; Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.; German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany., Günther S; German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany.; Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany., Looso M; German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany.; Bioinformatics Core Unit (BCU), Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany., Detleffsen J; German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany.; Bioinformatics Core Unit (BCU), Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany., Stainier DYR; Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.; German Centre for Cardiovascular Research (DZHK) Partner Site Rhine-Main, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.; Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany., Marín-Juez R; Centre Hospitalier Universitaire Sainte-Justine Research Center, 3175 Chemin de la Côte-Sainte-Catherine, H3T 1C5 Montréal, QC, Canada.; Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, H3T 1J4 Montréal, QC, Canada.
Jazyk:	angličtina
Zdroj:	Development (Cambridge, England) [Development] 2024 Dec 01; Vol. 151 (23). Date of Electronic Publication: 2024 Nov 29.
DOI:	10.1242/dev.203028
Abstrakt:	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. Competing Interests: Competing interests The authors declare no competing or financial interests. (© 2024. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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