VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart

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 and Alitalo, Kari (2014). VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart. EMBO molecular medicine, 6(3), pp. 307-321. EMBO Press 10.1002/emmm.201303147

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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.

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