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Dev Cell. 2019 Nov 18;51(4):503-515.e4. doi: 10.1016/j.devcel.2019.10.019.

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

Author information

1
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany; German Center of Cardiovascular Research (DZHK), Partner site RheinMain, 60590 Frankfurt am Main, Germany. Electronic address: ruben.marin-juez@mpi-bn.mpg.de.
2
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany; German Center of Cardiovascular Research (DZHK), Partner site RheinMain, 60590 Frankfurt am Main, Germany.
3
German Center of Cardiovascular Research (DZHK), Partner site RheinMain, 60590 Frankfurt am Main, Germany; Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60590 Frankfurt am Main, Germany.
4
Regeneration Next, Duke University, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
5
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany; German Center of Cardiovascular Research (DZHK), Partner site RheinMain, 60590 Frankfurt am Main, Germany. Electronic address: didier.stainier@mpi-bn.mpg.de.

Abstract

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.

KEYWORDS:

Apelin; Cxcl12/Cxcr4; Vegfa; coronaries; endocardium; epicardium; heart regeneration; hypoxia; revascularization; zebrafish

PMID:
31743664
PMCID:
PMC6982407
[Available on 2020-11-18]
DOI:
10.1016/j.devcel.2019.10.019

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