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VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart Kivela R; Bry M; Robciuc MR; Rasanen M; Taavitsainen M; Silvola JM; Saraste A; Hulmi JJ; Anisimov A; Mayranpaa MI; Lindeman JH; Eklund L; Hellberg S; Hlushchuk R; Zhuang ZW; Simons M; Djonov V; Knuuti J; Mervaala E; Alitalo KEMBO Mol Med 2014[Mar]; 6 (3): 307-21Angiogenic 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.|Adenoviridae/genetics[MESH]|Animals[MESH]|Genetic Vectors/metabolism[MESH]|Heart/diagnostic imaging[MESH]|Humans[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Models, Animal[MESH]|Myocardial Infarction/pathology[MESH]|Myocardial Ischemia/*prevention & control[MESH]|Myocardium/*metabolism[MESH]|Myocytes, Cardiac/metabolism[MESH]|Rats[MESH]|Rats, Sprague-Dawley[MESH]|Rats, Transgenic[MESH]|Rats, Wistar[MESH]|Signal Transduction[MESH]|Tomography, X-Ray Computed[MESH]|Up-Regulation[MESH]|Vascular Endothelial Growth Factor B/deficiency/genetics/*metabolism[MESH] |
