Kivelä Riikka, Bry Maija, Robciuc Marius R, Räsänen Markus, Taavitsainen Miia, Silvola Johanna M U, Saraste Antti, Hulmi Juha J, Anisimov Andrey, Mäyränpää Mikko I, Lindeman Jan H, Eklund Lauri, Hellberg Sanna, Hlushchuk Ruslan, Zhuang Zhen W, Simons Michael, Djonov Valentin, Knuuti Juhani, Mervaala Eero, Alitalo Kari
Wihuri Research Institute and Translational Cancer Biology Research Program, University of Helsinki, Helsinki, Finland.
EMBO Mol Med. 2014 Mar;6(3):307-21. doi: 10.1002/emmm.201303147. Epub 2014 Jan 21.
Angiogenic growth factors have recently been linked to tissue metabolism. We have used genetic gain- and loss-of function models to elucidate the effects and mechanisms of action of vascular endothelial growth factor-B (VEGF-B) in the heart. A cardiomyocyte-specific VEGF-B transgene induced an expanded coronary arterial tree and reprogramming of cardiomyocyte metabolism. This was associated with protection against myocardial infarction and preservation of mitochondrial complex I function upon ischemia-reperfusion. VEGF-B increased VEGF signals via VEGF receptor-2 to activate Erk1/2, which resulted in vascular growth. Akt and mTORC1 pathways were upregulated and AMPK downregulated, readjusting cardiomyocyte metabolic pathways to favor glucose oxidation and macromolecular biosynthesis. However, contrasting with a previous theory, there was no difference in fatty acid uptake by the heart between the VEGF-B transgenic, gene-targeted or wildtype rats. Importantly, we also show that VEGF-B expression is reduced in human heart disease. Our data indicate that VEGF-B could be used to increase the coronary vasculature and to reprogram myocardial metabolism to improve cardiac function in ischemic heart disease.
血管生成生长因子最近被认为与组织代谢有关。我们利用基因功能获得和缺失模型来阐明血管内皮生长因子B（VEGF-B）在心脏中的作用及其作用机制。心肌细胞特异性VEGF-B转基因可诱导冠状动脉树扩张并使心肌细胞代谢重编程。这与预防心肌梗死以及在缺血再灌注时保护线粒体复合物I功能有关。VEGF-B通过VEGF受体2增加VEGF信号以激活Erk1/2，从而导致血管生长。Akt和mTORC1通路上调，AMPK下调，重新调整心肌细胞代谢途径以有利于葡萄糖氧化和大分子生物合成。然而，与之前的理论相反，VEGF-B转基因大鼠、基因靶向大鼠或野生型大鼠的心脏对脂肪酸的摄取没有差异。重要的是，我们还表明，在人类心脏病中VEGF-B的表达会降低。我们的数据表明，VEGF-B可用于增加冠状动脉血管系统并使心肌代谢重编程，以改善缺血性心脏病中的心脏功能。
