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

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/FLT1, one can achieve more physiological VEGFA concentrations. We find that following cryoinjury, zebrafishflt1mutant hearts display enhanced coronary revascularization and endocardial expansion, increased cardiomyocyte dedifferentiation and proliferation, and decreased scarring. Suppressing Vegfa signaling inflt1mutants abrogates these beneficial effects offlt1deletion. Transcriptomic analyses of cryoinjured flt1 mutant hearts reveal enhanced endothelial MAPK/ERK signaling and downregulation of the transcription factor geneegr3. Using newly generated genetic tools, we observeegr3upregulation in the regenerating endocardium, and find that Egr3 promotes myofibroblast differentiation. These data indicate that with enhanced Vegfa bioavailability, the endocardium limits myofibroblast differentiation viaegr3downregulation, thereby providing a more permissive microenvironment for cardiomyocyte replenishment after injury.