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Preexisting endothelial cells mediate cardiac neovascularization after injury
Lingjuan He, … , Jeffery D. Molkentin, Bin Zhou
Lingjuan He, … , Jeffery D. Molkentin, Bin Zhou
Published August 1, 2017; First published June 26, 2017
Citation Information: J Clin Invest. 2017;127(8):2968-2981. https://doi.org/10.1172/JCI93868.
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Categories: Research Article Angiogenesis Vascular biology

Preexisting endothelial cells mediate cardiac neovascularization after injury

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Abstract

The mechanisms that promote the generation of new coronary vasculature during cardiac homeostasis and after injury remain a fundamental and clinically important area of study in the cardiovascular field. Recently, it was reported that mesenchymal-to-endothelial transition (MEndoT) contributes to substantial numbers of coronary endothelial cells after myocardial infarction. Therefore, the MEndoT has been proposed as a paradigm mediating neovascularization and is considered a promising therapeutic target in cardiac regeneration. Here, we show that preexisting endothelial cells mainly beget new coronary vessels in the adult mouse heart, with essentially no contribution from other cell sources through cell-lineage transdifferentiation. Genetic-lineage tracing revealed that cardiac fibroblasts expand substantially after injury, but do not contribute to the formation of new coronary blood vessels, indicating no contribution of MEndoT to neovascularization. Moreover, genetic-lineage tracing with a pulse-chase labeling strategy also showed that essentially all new coronary vessels in the injured heart are derived from preexisting endothelial cells, but not from other cell lineages. These data indicate that therapeutic strategies for inducing neovascularization should not be based on targeting presumptive lineage transdifferentiation such as MEndoT. Instead, preexisting endothelial cells appear more likely to be the therapeutic target for promoting neovascularization and driving heart regeneration after injury.

Authors

Lingjuan He, Xiuzhen Huang, Onur Kanisicak, Yi Li, Yue Wang, Yan Li, Wenjuan Pu, Qiaozhen Liu, Hui Zhang, Xueying Tian, Huan Zhao, Xiuxiu Liu, Shaohua Zhang, Yu Nie, Shengshou Hu, Xiang Miao, Qing-Dong Wang, Fengchao Wang, Ting Chen, Qingbo Xu, Kathy O. Lui, Jeffery D. Molkentin, Bin Zhou

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Figure 1

COL1A2+ fibroblasts do not adopt the endothelial cell fate after injury.

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COL1A2+ fibroblasts do not adopt the endothelial cell fate after injury....
(A) Models explaining new vessel sources: MEndoT and self-expansion. CoECs, coronary endothelial cells. (B) Z-stack confocal images of heart sections stained for tdTomato, PECAM, and PDGFRA. Col1a2-CreER R26R-tdTomato mice were treated with tamoxifen 2 weeks before analysis. YZ indicates signals from dotted lines on Z-stack images. Yellow arrowheads indicate PDGFRA+tdTomato+ fibroblasts; white arrowheads indicate PECAM+tdTomato– endothelial cells. (C) Immunostaining for tdTomato, PDGFRA, and PECAM on sections of postinjury hearts. tdTomato+ cells express fibroblast marker PDGFRA+ (yellow arrowheads), but not endothelial cell marker PECAM (white arrowheads). (D) Flow cytometric analysis of percentage of PECAM+ endothelial cells labeled by Col1a2-CreER transgene (tdTomato+). (E) Immunostaining for VE-CAD and tdTomato on sections of injured heart. tdTomato+ cells (yellow arrowheads) are close to, but were not identified as VE-CAD+ endothelial cells (white arrowheads) in the injured heart. (F) Immunostaining for VEGFR2 and tdTomato on heart sections perfused with FITC-labeled BS1 lectin. tdTomato+ cells (yellow arrowheads) are not VEGFR2+lectin+ vascular endothelial cells (white arrowheads). Scale bars: 100 μm. Each image is representative of 4 individual hearts.
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ISSN: 0021-9738 (print), 1558-8238 (online)

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