Vascular endothelial growth factor B controls endothelial fatty acid uptake.
The vascular endothelial growth factors (VEGFs) are major angiogenic regulators and are involved in several aspects of endothelial cell physiology. However, the detailed role of VEGF-B in blood vessel function has remained unclear. Here we show that VEGF-B has an unexpected role in endothelial targeting of lipids to peripheral tissues. Dietary lipids present in circulation have to be transported through the vascular endothelium to be metabolized by tissue cells, a mechanism that is poorly understood. Bioinformatic analysis showed that Vegfb was tightly co-expressed with nuclear-encoded mitochondrial genes across a large variety of physiological conditions in mice, pointing to a role for VEGF-B in metabolism. VEGF-B specifically controlled endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. As a consequence, Vegfb(-/-) mice showed less uptake and accumulation of lipids in muscle, heart and brown adipose tissue, and instead shunted lipids to white adipose tissue. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium. The co-expression of VEGF-B and mitochondrial proteins introduces a novel regulatory mechanism, whereby endothelial lipid uptake and mitochondrial lipid use are tightly coordinated. The involvement of VEGF-B in lipid uptake may open up the possibility for novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.
Tissue Biology Group, Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Carolina E
CE
Hagberg
Annelie
A
Falkevall
Xun
X
Wang
Erik
E
Larsson
Jenni
J
Huusko
Ingrid
I
Nilsson
Laurens A
LA
van Meeteren
Erik
E
Samen
Li
L
Lu
Maarten
M
Vanwildemeersch
Joakim
J
Klar
Guillem
G
Genove
Kristian
K
Pietras
Sharon
S
Stone-Elander
Lena
L
Claesson-Welsh
Seppo
S
Ylä-Herttuala
Per
P
Lindahl
Ulf
U
Eriksson
D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology / Q000378:metabolism*; D050612:Fatty Acid Transport Proteins / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D015398:Signal Transduction; D014158:Transcription, Genetic; D042561:Vascular Endothelial Growth Factor B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D042561:Vascular Endothelial Growth Factor B; C467482:vascular endothelial growth factor B, mouse; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1