title: Fast revascularization of the injured area is essential to support zebrafish heart regeneration.
abstract: Zebrafish have a remarkable capacity to regenerate their heart. Efficient replenishment of lost tissues requires the activation of different cell types including the epicardium and endocardium. A complex set of processes is subsequently needed to support cardiomyocyte repopulation. Previous studies have identified important determinants of heart regeneration; however, to date, how revascularization of the damaged area happens remains unknown. Here, we show that angiogenic sprouting into the injured area starts as early as 15 h after injury. To analyze the role of vegfaa in heart regeneration, we used vegfaa mutants rescued to adulthood by vegfaa mRNA injections at the one-cell stage. Surprisingly, vegfaa mutants develop coronaries and revascularize after injury. As a possible explanation for these observations, we find that vegfaa mutant hearts up-regulate the expression of potentially compensating genes. Therefore, to overcome the lack of a revascularization phenotype in vegfaa mutants, we generated fish expressing inducible dominant negative Vegfaa. These fish displayed minimal revascularization of the damaged area. In the absence of fast angiogenic revascularization, cardiomyocyte proliferation did not occur, and the heart failed to regenerate, retaining a fibrotic scar. Hence, our data show that a fast endothelial invasion allows efficient revascularization of the injured area, which is necessary to support replenishment of new tissue and achieve efficient heart regeneration. These findings revisit the model where neovascularization is considered to happen concomitant with the formation of new muscle. Our work also paves the way for future studies designed to understand the molecular mechanisms that regulate fast revascularization.
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany; ruben.marin-juez@mpi-bn.mpg.de didier.stainier@mpi-bn.mpg.de.
authors.forename: Rubén
authors.initials: R
authors.lastname: Marín-Juez
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Michele
authors.initials: M
authors.lastname: Marass
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gauvrit
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Shih-Lei
authors.initials: SL
authors.lastname: Lai
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143-3120.
authors.forename: Stefan C
authors.initials: SC
authors.lastname: Materna
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA 94143-3120; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany; ruben.marin-juez@mpi-bn.mpg.de didier.stainier@mpi-bn.mpg.de.
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D003331:Coronary Vessels / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000503:physiopathology*; D018869:Heat-Shock Response; D009154:Mutation / Q000235:genetics; D009204:Myocardial Revascularization; D032383:Myocytes, Cardiac / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010496:Pericardium / Q000473:pathology; D012038:Regeneration / Q000502:physiology*; D013897:Thoracic Duct / Q000473:pathology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D029961:Zebrafish Proteins
keywords: VEGF; angiogenesis; coronaries; heart regeneration; revascularization