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Nature. 2014 Oct 30;514(7524):585-90. doi: 10.1038/nature13839. Epub 2014 Oct 15.

Mesenchymal-endothelial transition contributes to cardiac neovascularization.

Author information

1
Department of Cell Biology &Physiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
2
1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Eli and Edythe Broad Institute of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA [4] Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, California 90095, USA [5] Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA [6] Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.
3
1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [4] Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
4
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
5
Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
6
Department of Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
7
1] Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Molecular Biology Institute, University of California, Los Angeles, California 90095, USA [4] Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [5] Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
8
1] Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [2] Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA [3] Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.

Abstract

Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial-cell-like phenotype after acute ischaemic cardiac injury. Fibroblast-derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal-to-endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.

PMID:
25317562
PMCID:
PMC4214889
DOI:
10.1038/nature13839
[Indexed for MEDLINE]
Free PMC Article

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