In vivo transduction of ETV2 improves cardiac function and induces vascular regeneration following myocardial infarction

• Type of Material: Article
• Authors: Dong-Hoo Lee, Emory University; Sunghun Lee, City University of Hong Kong; Bong-Woo Park, Catholic University of Korea; Riyoun Kim, City University of Hong Kong; Anh Duc Hoang, City University of Hong Kong; Sang-Keun Woo, Korea Institute of Radiological & Medical Sciences; Wenjun Xiong, City University of Hong Kong; Yong Jin Lee, Korea Institute of Radiological & Medical Sciences; Kiwon Ban, City University of Hong Kong; Hun-Jun Park, Catholic University of Korea
• Language: English
• Date: 2019-02-12
• Publisher: Springer Nature [academic journals on nature.com]: Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2019
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s12276-019-0206-6
• Title of Journal or Parent Work: Experimental and Molecular Medicine
• ISSN: 1226-3613
• Volume: 51
• Issue: 2
• Start Page: 13
• End Page: 13
• Grant/Funding Information: This study was supported by a CityU Start-up Grant (7200492) and the CityU Research Project (9610355 to K.B).; This study was also supported by a National Research Foundation of Korea (NRF) grant (2016R1C1B2015529), a Bio & Medical Technology Development Program grant (NRF-2017M3A9B3061954) and the Technology Innovation Program (10052980 to H.J.P.) funded by the Ministry of Trade, Industry and Energy (MOTIE), Republic of Korea.
• Keywords: HEART; DIRECT CONVERSION; Life Sciences & Biomedicine; REGIONAL FUNCTION; Research & Experimental Medicine; Biochemistry & Molecular Biology; FIBROBLASTS; PLURIPOTENT STEM-CELLS; ANGIOGENESIS; Medicine, Research & Experimental; Science & Technology; CARDIOMYOCYTES; GENE-TRANSFER; ENDOTHELIAL-CELLS; DISEASE
• Research Categories: Engineering, Biomedical; Health Sciences, Medicine and Surgery

Abstract

Vascular regeneration in ischemic hearts has been considered a target for new therapeutic strategies. It has been reported that ETV2 is essential for vascular development, injury-induced neovascularization and direct cell reprogramming of non-endothelial cells into endothelial cells. Thus, the objective of this study was to explore the therapeutic potential of ETV2 in murine models of myocardial infarction in vivo. Direct myocardial delivery of lentiviral ETV2 into rodents undergoing myocardial infarction dramatically upregulated the expression of markers for angiogenesis as well as anti-fibrosis and anti-inflammatory factors in vivo. Consistent with these findings, echocardiography showed significantly improved cardiac function in hearts with induced myocardial infarction upon ETV2 injection compared to that in the control virus-injected group as determined by enhanced ejection fraction and fractional shortening. In addition, ETV2-injected hearts were protected against massive fibrosis with a remarkable increase in capillary density. Interestingly, major fractions of capillaries were stained positive for ETV2. In addition, ECs infected with ETV2 showed enhanced proliferation, suggesting a direct role of ETV2 in vascular regeneration in diseased hearts. Furthermore, culture media from ETV2-overexpressing cardiac fibroblasts promoted endothelial cell migration based on scratch assay. Importantly, intramyocardial injection of the adeno-associated virus form of ETV2 into rat hearts with induced myocardial infarction designed for clinical applicability consistently resulted in significant augmentation of cardiac function. We provide compelling evidence that ETV2 has a robust effect on vascular regeneration and enhanced cardiac repair after myocardial infarction, highlighting a potential therapeutic function of ETV2 as an efficient means to treat failing hearts.