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Vascular endothelial growth factor B controls endothelial fatty acid uptake

Abstract

The vascular endothelial growth factors (VEGFs) are major angiogenic regulators and are involved in several aspects of endothelial cell physiology1. However, the detailed role of VEGF-B in blood vessel function has remained unclear2,3. 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 understood4. 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.

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Figure 1: Coordinated expression of Vegfb and nuclear-encoded mitochondrial genes.
Figure 2: VEBF-B regulates FATP transcription through signalling via VEGFR1 and NRP1.
Figure 3: VEGF-B induces trans-endothelial lipid transport.
Figure 4: Reduced peripheral lipid uptake and storage in Vegfb -/- and Nrp1-EC -/- mice.

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Acknowledgements

We thank S. Rezian for technical assistance; W. C. Claycomb for the gift of the HL-1 cardiomyocytes; M. McMahon for the TIME cells; A. Nash for the 2H10 anti-VEGF-B monoclonal antibody; K. Plate and M. Shibuya for Flt1-TK-/- mouse organs; and D. Cheresh for the EC-SCL-Cre-ERT Nrp1fl/fl mice. C.E.H. was supported by Wilhelm och Else Stockmanns Stiftelse, and by Frans Wilhelm och Waldemar von Frenckells fond. E.L. was supported by Lymphangiogenomics, an Integrated Project funded by the European Commission within its FP6 Programme, under the thematic area ‘Life sciences, genomics and biotechnology for health’, contract number LSHG-CT-2004-503573. L.A.v.M. was supported by The Dutch Cancer Society. This study was supported by The Novo Nordisk Foundation, The Swedish Cancer Foundation, The Swedish Research Council, Dr. Peter Wallenbergs Foundation for Economics and Technology, The LeDucq Foundation, The Swedish Brain Foundation and Hållstens Forskningsstiftelse, and the Karolinska Institutet.

Author Contributions C.E.H. performed in vivo experiments, qPCR analyses, in vitro and in vivo lipid uptake and transport assays, cloning, siRNA assay, isolation of endothelial cells, IHC, ORO and haematoxylin and eosin stainings, designed experiments and prepared the manuscript; A.F. performed cell stimulations, receptor experiments, western blotting and qPCR analyses, IHC and ORO staining of heart tissue, and helped write the paper; X.W. assisted in in vivo experiments, performed NCBI bioinformatics, plasma analyses, C2C12 β-oxidation experiment and analysis of mtDNA; E.L. designed and performed bioinformatics analyses and interpreted results; J.H. designed and performed the adenoviral experiments; I.N. performed adenoviral rescue experiments; L.A.v.M. performed EC-SCL-Cre-ERT Nrp1fl/fl mice experiments; E.S., L.L. and S.S.-E. designed and performed the PET scan and interpreted results; M.V. aided with cloning and performed plasma hVEGF-B ELISA measurements; J.K. directed experiments and interpreted results; G.G. directed the MRI scan; K.P. assisted in endothelial cell isolation experiments and interpreted results; L.C.-W., S.Y.-H. and P.L. designed experiments, interpreted results and helped write the paper; U.E. designed the study, analysed the data and wrote the paper. All authors discussed the results and commented on the manuscript.

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Hagberg, C., Falkevall, A., Wang, X. et al. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464, 917–921 (2010). https://doi.org/10.1038/nature08945

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