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.
Highlights
Ischemic heart disease (IHD) is one of the most devastating diseases, afflicting ~7.4 million people worldwide[1]
In vivo transduction of ETV2 into myocardial infarction (MI)-induced hearts To investigate the applicability of ETV2 as a therapeutic agent for IHD, we employed a murine model of MI induced by permanent ligation of the left anterior descending (LAD) artery[31,32,33]
To determine the therapeutic effects of ETV2 overexpression in MI hearts, we performed echocardiography on a weekly basis to measure cardiac remodeling and function in Effects of ETV2 on vascular regeneration in MI hearts Since ETV2 was found to be a strong inducer of neovascularization that could significantly contribute to cardiac regeneration following MI, we evaluated the effects of ETV2 on vascular regeneration in MI hearts
Summary
Ischemic heart disease (IHD) is one of the most devastating diseases, afflicting ~7.4 million people worldwide[1]. Myocardial infarction (MI), the most serious clinical manifestation of IHD, is caused by arterial coronary occlusion (i.e., ischemia), resulting in massive loss of cardiomyocytes and vasculatures[2]. High mortality and morbidity from IHD are mainly ascribed to the limited ability of proliferation of adult cardiomyocytes (CMs) and insufficient coronary vasculature in infarcted hearts[3,4]. Pro-angiogenic factors such as VEGF, FGF, and HGF have the focus, among other options, due to their strong ability to induce vessel formation. Findings from a zebrafish study demonstrated that defective angiogenic signaling limited CM proliferation post heart injury, further suggesting neovascularization as an effective therapeutic strategy to treat injured hearts[14]. Identifying potential endothelial master regulator(s) and investigating their functional roles in the vascular system would be of significant importance to developing potent and specific therapeutic vehicles for treating IHD
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