Coronary Revascularization During Heart Regeneration Is Regulated by Epicardial and Endocardial Cues and Forms a Scaffold for Cardiomyocyte Repopulation

• Published in: Developmental cell Vol. 51; no. 4; pp. 503 - 515.e4
• Main Authors: Marín-Juez, Rubén, El-Sammak, Hadil, Helker, Christian S.M., Kamezaki, Aosa, Mullapuli, Sri Teja, Bibli, Sofia-Iris, Foglia, Matthew J., Fleming, Ingrid, Poss, Kenneth D., Stainier, Didier Y.R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.11.2019
• Subjects: Apelin; coronaries; Cxcl12/Cxcr4; endocardium; epicardium; heart regeneration; hypoxia; revascularization; Vegfa; zebrafish; hypoxia; revascularization; heart regeneration; Cxcl12/Cxcr4; endocardium; Vegfa; epicardium; zebrafish; coronaries; Apelin
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2019.10.019

Defective coronary network function and insufficient blood supply are both cause and consequence of myocardial infarction. Efficient revascularization after infarction is essential to support tissue repair and function. Zebrafish hearts exhibit a remarkable ability to regenerate, and coronary revascularization initiates within hours of injury, but how this process is regulated remains unknown. Here, we show that revascularization requires a coordinated multi-tissue response culminating with the formation of a complex vascular network available as a scaffold for cardiomyocyte repopulation. During a process we term “coronary-endocardial anchoring,” new coronaries respond by sprouting (1) superficially within the regenerating epicardium and (2) intra-ventricularly toward the activated endocardium. Mechanistically, superficial revascularization is guided by epicardial Cxcl12-Cxcr4 signaling and intra-ventricular sprouting by endocardial Vegfa signaling. Our findings indicate that the injury-activated epicardium and endocardium support cardiomyocyte replenishment initially through the guidance of coronary sprouting. Simulating this process in the injured mammalian heart should help its healing. [Display omitted] •Regenerating coronaries respond by sprouting superficially and intra-ventricularly•Superficial revascularization is regulated by epicardial Cxcl12/Cxcr4 signaling•Intra-ventricular revascularization is regulated by endocardial Vegfa signaling•Regenerating coronaries provide a scaffold available for cardiomyocyte repopulation Marín-Juez et al. find that the epicardium and endocardium help to reestablish the coronary network after cardiac injury in adult zebrafish. Coronary revascularization is regulated by the coordinated action of Cxcl12/Cxcr4 and Vegfa signaling. Regenerating coronaries provide a scaffold for cardiomyocyte repopulation. Perturbing Cxcl12/Cxcr4 or Vegfa signaling impairs coronary revascularization and cardiomyocyte repopulation.