Mesenchymal–endothelial transition contributes to cardiac neovascularization

Eric Ubil, Jinzhu Duan, Indulekha C. L. Pillai, Manuel Rosa-Garrido, Yong Wu, Francesca Bargiacchi, Yan Lu, Seta Stanbouly, Jie Huang, Mauricio Rojas, Thomas M. Vondriska, Enrico Stefani and Arjun Deb ()
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Eric Ubil: School of Medicine, University of North Carolina
Jinzhu Duan: David Geffen School of Medicine, University of California
Indulekha C. L. Pillai: David Geffen School of Medicine, University of California
Manuel Rosa-Garrido: David Geffen School of Medicine, University of California
Yong Wu: David Geffen School of Medicine, University of California
Francesca Bargiacchi: School of Medicine, University of North Carolina
Yan Lu: David Geffen School of Medicine, University of California
Seta Stanbouly: David Geffen School of Medicine, University of California
Jie Huang: David Geffen School of Medicine, University of California
Mauricio Rojas: McAllister Heart Institute, University of North Carolina
Thomas M. Vondriska: David Geffen School of Medicine, University of California
Enrico Stefani: Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California
Arjun Deb: David Geffen School of Medicine, University of California

Nature, 2014, vol. 514, issue 7524, 585-590

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13839

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