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Vascular endothelial growth factor B controls endothelial fatty acid uptake
Carolina E. Hagberg1,2, Annelie Falkevall1,2, Xun Wang1,2, Erik Larsson3, Jenni Huusko4, Ingrid Nilsson1, Laurens A. van Meeteren5, Erik Samen6,7, Li Lu7, Maarten Vanwildemeersch1,2, Joakim Klar2,5, Guillem Genove8, Kristian Pietras1,2, Sharon Stone-Elander6,7, Lena Claesson-Welsh5, Seppo Yl?-Herttuala4, Per Lindahl3,9 & Ulf Eriksson1,2
Tissue Biology Group, Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, SwedenLudwig Institute for Cancer Research Ltd, Stockholm Branch, Karolinska Institutet, Box 240, SE-171 77 Stockholm, Sweden
Institute of Biomedicine, University of Gothenburg, Box 440, SE-405 30 Gothenburg, Sweden
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, Box 1627, FIN-70211 Kuopio, Finland
Uppsala University, Department of Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden
Karolinska Pharmacy, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden
Clinical Neurosciences, Karolinska Institutet, SE-171 76 Stockholm, Sweden
Laboratory of Vascular Biology, Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Wallenberg Laboratory for Cardiovascular Research, Bruna Str?ket 16, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden
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.
