VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart.
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.
Wihuri Research Institute and Translational Cancer Biology Research Program, University of Helsinki, Helsinki, Finland.
Riikka
R
Kivelä
Maija
M
Bry
Marius R
MR
Robciuc
Markus
M
Räsänen
Miia
M
Taavitsainen
Johanna M U
JM
Silvola
Antti
A
Saraste
Juha J
JJ
Hulmi
Andrey
A
Anisimov
Mikko I
MI
Mäyränpää
Jan H
JH
Lindeman
Lauri
L
Eklund
Sanna
S
Hellberg
Ruslan
R
Hlushchuk
Zhen W
ZW
Zhuang
Michael
M
Simons
Valentin
V
Djonov
Juhani
J
Knuuti
Eero
E
Mervaala
Kari
K
Alitalo
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D005822:Genetic Vectors / Q000378:metabolism; D006321:Heart / Q000000981:diagnostic imaging; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017208:Rats, Wistar; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed; D015854:Up-Regulation; D042561:Vascular Endothelial Growth Factor B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D042561:Vascular Endothelial Growth Factor B