Alternative titles; symbols
HGNC Approved Gene Symbol: VEGFB
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:64,234,584-64,239,264 (from NCBI)
Vascular endothelial growth factor B (VEGFB) signals via the endothelial receptor VEGFR1 (165070) and is a regulator of blood vessel physiology, with a role in endothelial targeting of lipids to peripheral tissues (summary by Hagberg et al., 2010).
Grimmond et al. (1996) cloned and characterized a member of the vascular endothelial growth factor (VEGF; 192240) gene family, which they designated VRF for VEGF-related factor. By sequencing of cDNAs from a human fetal brain library and RT-PCR products from normal and tumor tissue cDNA pools, they identified 2 alternatively spliced messages with open reading frames of 621 and 564 bp, respectively. The predicted 186- and 167-amino acid polypeptides differ at their carboxyl ends, resulting from a shift in the open reading frame. Both isoforms show strong homology to VEGF at their amino termini, but only the shorter isoform maintained homology to VEGF at its carboxyl terminus and conserved all 16 cysteine residues of the 165-amino acid form of VEGF. VRF was predicted to contain a signal peptide, suggesting to Grimmond et al. (1996) that it may be a secreted factor. The investigators found that VRF is ubiquitously expressed as 2 transcripts of 2.0 and 5.5 kb and that the level of expression is similar among normal and malignant tissues.
Olofsson et al. (1996) showed that mouse and human VEGFB-167 share 88% sequence identity. By Northern blot analysis of human tissues, they identified a 1.4-kb VEGFB-167 transcript expressed in heart, skeletal muscle, pancreas, and prostate.
Olofsson et al. (1996) showed that the C termini of VEGFB-167, VEGF, and other related growth factors contain a strongly basic cysteine-rich heparin binding domain, whereas the C terminus of VEGFB-186 has no heparin binding domain, is less basic and more hydrophobic, and has no similarity to any published sequence. Olofsson et al. (1996) performed Northern blot analysis using a probe specific to VEGFB-186 and found a 1.4-kb transcript expressed in a pattern nearly identical to that described by Olofsson et al. (1996) for VEGFB-167.
Grimmond et al. (1996) found that the protein coding region of VRF, which spans approximately 5 kb, is composed of 8 exons that range in size from 36 to 431 bp. Exons 6 and 7 are contiguous and the 2 isoforms of VRF arise through alternate splicing of exon 6.
In a large panel of tumors of endocrine and nonendocrine origin, Grimmond et al. (1996) observed a reduction in expression of VRF only in those endocrine tumors known to be hemizygous for 11q. The authors pointed out that the putative role of VRF as a growth factor makes it an unlikely candidate for the MEN1 tumor suppressor gene.
Olofsson et al. (1996) noted that VEGF and VEGFB-167 are coexpressed in many tissues. In situ hybridization revealed that VEGFB-167 is expressed predominantly in muscular tissues and that expression can be detected at an early stage during embryonic development. Expression of VEGF and VEGFB-167 in transfected human embryonic 293EBNA cells and subsequent analysis by SDS/PAGE showed that VEGFB-167 forms cell-associated disulfide-linked dimers and can form heterodimers with VEGF. Olofsson et al. (1996) demonstrated that VEGFB-167 can act as an endothelial cell growth factor.
Olofsson et al. (1996) reported the expression of VEGF and VEGFB-186 in transfected human embryonic 293EBNA cells; subsequent analysis by SDS/PAGE revealed that VEGFB-186 is secreted as a disulfide-linked homodimer and that, like VEGFB-167, this isoform can form disulfide-linked heterodimers with VEGF. Expression experiments using COS cells and digestion with neuraminidase also revealed that VEGFB-186 undergoes O-linked glycosylation during its intracellular transport and secretion.
Silvestre et al. (2003) analyzed the angiogenic effect of VEGFB in 2 different models of angiogenesis: an in vivo model of Matrigel and a mouse model of surgically induced hindlimb ischemia. They demonstrated that VEGFB, in part through its receptor VEGFR1 (165070), promotes angiogenesis in association with activation of AKT (164730) and endothelial nitric oxide synthase (eNOS; 163729)-related pathways.
Hagberg et al. (2010) showed that VEGFB has a role in endothelial targeting of lipids to peripheral tissues. Dietary lipids present in circulation must be transported through the vascular endothelium to be metabolized by tissue cells. Bioinformatic analysis showed that Vegfb was tightly coexpressed with nuclear-encoded mitochondrial genes across a large variety of physiologic conditions in mice, pointing to a role for VEGFB in metabolism. VEGFB 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 VEGFR1 and neuropilin-1 (NRP1; 602069) expressed by the endothelium. The coexpression of VEGFB and mitochondrial proteins introduces a novel regulatory mechanism, whereby endothelial lipid uptake and mitochondrial lipid use are tightly coordinated.
Grimmond et al. (1996) showed that the VRF gene is located within a cosmid (the D11S750 locus) which maps to 11q13 in the region of multiple endocrine neoplasia type 1 (MEN1; 131100). PCR-based mapping against a human/hamster hybrid panel confirmed single gene copy number and localization to 11q13.
By FISH, Gerace et al. (2001) mapped the Vegfb gene to mouse chromosome 19B.
Bellomo et al. (2000) described the Vegfb -/- mouse. Unlike Vegfa -/- mice, which die during embryogenesis, Vegfb -/- mice are healthy and fertile. Although Vegfb -/- hearts appeared morphologically and functionally normal in unstressed mice, Bellomo et al. (2000) found that Vegfb -/- hearts were marginally smaller and displayed vascular dysfunction after coronary occlusion and impaired recovery from experimentally induced myocardial ischemia.
Mould et al. (2003) studied 2 mouse models of arthritis, antigen- and collagen-induced arthritis, in Vegfb knockout mice. Knee joint swelling, synovial inflammation, and inflammation-associated vessel density in arthritic joints were reduced in Vegfb -/- mice compared to wildtype mice. Mould et al. (2003) concluded that the reduction in inflammation-associated synovial angiogenesis in Vegfb -/- mice implicated VEGFB in pathologic vascular remodeling in inflammatory arthritis.
Hagberg et al. (2012) showed that decreased Vegfb signaling in rodent models of type 2 diabetes (see 125853) restores insulin sensitivity and improves glucose tolerance. Genetic deletion of Vegfb in diabetic db/db (leptin receptor-null; see 601007) mice prevented ectopic lipid deposition, increased muscle glucose uptake, and maintained normoglycemia. Pharmacologic inhibition of Vegfb signaling by antibody administration to db/db mice enhanced glucose tolerance, preserved pancreatic islet architecture, improved B-cell function, and ameliorated dyslipidemia, key elements of type 2 diabetes and the metabolic syndrome. The potential use of VEGFB neutralization in type 2 diabetes was further elucidated in rats fed a high-fat diet, in which it normalized insulin sensitivity and increased glucose uptake in skeletal muscle and heart. Hagberg et al. (2012) concluded that the vascular endothelium can function as an efficient barrier to excess muscle lipid uptake even under conditions of severe obesity and type 2 diabetes, and that this barrier can be maintained by inhibition of VEGFB signaling.
Bellomo, D., Headrick, J. P., Silins, G. U., Paterson, C. A., Thomas, P. S., Gartside, M., Mould, A., Cahill, M. M., Tonks, I. D., Grimmond, S. M., Townson, S., Wells, C., Little, M., Cummings, M. C., Hayward, N. K., Kay, G. F. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ. Res. 86: e29-e35, 2000. [PubMed: 10666423] [Full Text: https://doi.org/10.1161/01.res.86.2.e29]
Gerace, L, Cirenei, N., Cappelletti, M., Petraroli, R., Sebastiani, F., Marziliano, N. Assignment of the mouse Vegfb gene to mouse chromosome 19B by in situ hybridization. Cytogenet. Cell Genet. 95: 242-243, 2001. [PubMed: 12063409] [Full Text: https://doi.org/10.1159/000059355]
Grimmond, S., Lagercrantz, J., Drinkwater, C., Silins, G., Townson, S., Pollock, P., Gotley, D., Carson, E., Rakar, S., Nordenskjold, M., Ward, L., Hayward, N., Weber, G. Cloning and characterization of a novel human gene related to vascular endothelial growth factor. Genome Res. 6: 124-131, 1996. [PubMed: 8919691] [Full Text: https://doi.org/10.1101/gr.6.2.124]
Hagberg, C. E., Falkevall, A., Wang, X., Larsson, E., Huusko, J., Nilsson, I., van Meeteren, L. A., Samen, E., Lu, L., Vanwildemeersch, M., Klar, J., Genove, G., Pietras, K., Stone-Elander, S., Claesson-Welsh, L., Yia-Herttuala, S., Lindahl, P., Eriksson, U. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464: 917-921, 2010. [PubMed: 20228789] [Full Text: https://doi.org/10.1038/nature08945]
Hagberg, C. E., Mehlem, A., Falkevall, A., Muhl, L., Fam, B. C., Ortsater, H., Scotney, P., Nyqvist, D., Samen, E., Lu, L., Stone-Elander, S., Proietto, J., Andrikopoulos, S., Sjoholm, A., Nash, A., Eriksson, U. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature 490: 426-430, 2012. [PubMed: 23023133] [Full Text: https://doi.org/10.1038/nature11464]
Mould, A. W., Tonks, I. D., Cahill, M. M., Pettit, A. R., Thomas, R., Hayward, N. K., Kay, G. F. Vegfb gene knockout mice display reduced pathology and synovial angiogenesis in both antigen-induced and collagen-induced models of arthritis. Arthritis Rheum. 48: 2660-2669, 2003. [PubMed: 13130487] [Full Text: https://doi.org/10.1002/art.11232]
Olofsson, B., Pajusola, K., Kaipainen, A., von Euler, G., Joukov, V., Saksela, O., Orpana, A., Pettersson, R. F., Alitalo, K., Eriksson, U. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc. Nat. Acad. Sci. 93: 2576-2581, 1996. [PubMed: 8637916] [Full Text: https://doi.org/10.1073/pnas.93.6.2576]
Olofsson, B., Pajusola, K., von Euler, G., Chilov, D., Alitalo, K., Eriksson, U. Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. J. Biol. Chem. 271: 19310-19317, 1996. [PubMed: 8702615] [Full Text: https://doi.org/10.1074/jbc.271.32.19310]
Silvestre, J.-S., Tamarat, R., Ebrahimian, T. G., Le-Roux, A., Clergue, M., Emmanuel, F., Duriez, M., Schwartz, B., Branellec, D., Levy, B. I. Vascular endothelial growth factor-B promotes in vivo angiogenesis. Circ. Res. 93: 114-123, 2003. [PubMed: 12805240] [Full Text: https://doi.org/10.1161/01.RES.0000081594.21764.44]