The International Journal of Biochemistry & Cell Biology 33 (2001) 421–426
Molecules in focus
Novel VEGF family members: VEGF-B, VEGF-C and
VEGF-D
Xuri Li, Ulf Eriksson *
Ludwig Institute for Cancer Research, Stockholm Branch, Box 240, S-171 77 Stockholm, Sweden
Received 6 March 2000; accepted 23 January 2001
Abstract
Vascular endothelial growth factors (VEGFs) constitute a group of structurally and functionally related growth
factors that modulate many important physiological functions of endothelial cells. Currently, five different mam-
malian VEGFs have been identified and they all show unique temporal and spatial expression patterns, receptor
specificity and function. The VEGFs may play pivotal roles in formation of the vascular systems during embryonic
development, in regulation of capillary growth in normal and pathological conditions in adults, and in the
maintenance of the normal vasculature. In the future, the VEGFs and their receptors may become important
therapeutic tools in treatment of conditions characterized by aberrant or defective formation of blood vessels and
lymphatic vessels. ? 2001 Elsevier Science Ltd. All rights reserved.
Keywords: VEGF; Angiogenesis; Lymphangiogenesis; Growth factor
www.elsevier.com/locate/ijbcb
1. Introduction
Blood vessels are formed using two different
mechanisms, de novo formation of the primary
vascular plexa from differentiating endothelial cell
precursors during embryogenesis in a process re-
ferred to as vasculogenesis; and angiogenesis, the
sprouting or splitting of capillaries from pre-exist-
ing vessels [1].
The parental Vascular endothelial growth fac-
tor (VEGF) molecule (or VEGF-A) was discov-
ered more than a decade ago and has since then
been recognized as a major hypoxia-inducible
growth factor for blood vessel endothelial cells [2].
The recently discovered VEGFs, named VEGF-B,
VEGF-C and VEGF-D share structural features
typical of the VEGF family, but display different
biological activities, mainly owing to their differ-
ent specificities for the three known VEGF recep-
tors; VEGFR-1, VEGFR-2 and VEGFR-3 [3].
VEGF-B was serendipitously found in 1995 as
a partial mouse cDNA clone encoding a VEGF-
related peptide [4]. Independently, the VEGF-B
* Corresponding author.
E-mail address: ueri@licr.ki.se (U. Eriksson).
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PII: S1357-2725(01)00027-9

X. Li, U. Eriksson / The International Journal of Biochemistry & Cell Biology 33 (2001) 421–426422
gene was identified in a search for the gene in-
volved in multiple endocrine neoplasia type 1
(MEN1) located at chromosome 11q13.
VEGF-C was identified in 1996 as a factor able
to stimulate tyrosine phosphorylation of a recep-
tor tyrosine kinase, Flt4, (later referred to as
VEGFR-3) and then was isolated and its cDNA
cloned [5]. The identified molecule was a novel
homologue of VEGF and was denoted VEGF-C.
Independently, an expressed sequence tag (EST)
was found to encode the same protein.
VEGF-D was first isolated as a partial cDNA
from a differential display screening of murine
genes expressed in fibroblasts from normal mice
but not expressed in fibroblasts from mice carry-
ing a targeted inactivation of the c-fos gene [6].
The identified protein was first denoted c-fos-in-
duced growth factor, but was later renamed to
VEGF-D to indicate that it was a novel VEGF
homologue.
The placenta growth factor (PlGF) also belongs
to the VEGF family [7] and based on its binding
specificity to VEGFR-1, it appears to be a func-
tional homologue of VEGF-B, but it will not be
specifically discussed here. In addition, several
VEGF homologues encoded by different strains
of Orf viruses have recently been found. However,
these molecules are not likely to represent VEGFs
with mammalian counterparts, and will not be
covered here. In this review structural and func-
tional properties of the novel VEGFs, i.e. VEGF-
B, VEGF-C and VEGF-D will be summarized.
Fig. 1. Schematic illustration of the domain structures of the currently known members of the VEGF family, including the novel
VEGFs, VEGF-B, VEGF-C and VEGF-D. The different domain structures include the VEGF homology domain (in green), the
C-terminal regions containing the basic heparin-binding domains in some splice isoforms of VEGF, PlGF and VEGF-B (in dark
blue), the unique C-terminal domain in VEGF-B
186
(in red), the N-terminal propeptide domains (in light blue), and silk
domain-containing C-terminal propeptides in VEGF-C and D (in yellow). Note that the different domains are not drawn in scale.
The numbers to the right refer to the number of amino acids in the proteins shown.