VEGFD (c-fos induced growth factor (vascular endothelial growth factor D))

2012-05-01   Marina Rocchigiani , Salvatore Oliviero 

Department of Molecular Biology, University of Siena, Italy




Atlas Image


The VEGFD gene consists of 7 exons and spans 38865 bases on chromosome X in minus strand orientation.
The upstream promoter sequence does not contain a canonical TATA box. The promoter sequence contains an optimal AP-1 binding site at position -54 from the start site.


The mRNA transcribed from this gene is 2110 nucleotides long.


Atlas Image
The VEGF-D chain is a secreted protein synthesised as 354 amino acid precursor containing a signal peptide (AA:1-21), an N-propeptide (AA:22-88), a VHD (VEGF Homology Domain, AA:89-205) and a C-propeptide (AA:206-354).


VEGF-D is a member of the Platelet-Derived Growth Factor/Vascular Endothelial Growth Factor (PDGF/VEGF) family that contains a conserved domain of eight cysteine residues forming the typical cystine-knot structure involved in the formation of the biologically active dimer (Debinski et al., 2001; Rocchigiani et al., 1998; Yamada et al., 1997; Joukov et al., 1996). The human VEGF family consists of 5 members: VEGF-A, VEGF-B, VEGF-C, VEGF-D and Placental Growth Factor (PlGF) which differ in their ability to bind to VEGF receptors that are primarily expressed in endothelial cells: VEGFR1 (Flt1), VEGFR2 (KDR, Flk1), VEGFR3 (Flt4), neuropilin-1 and neuropilin-2. VEGFA binds to VEGFR1, VEGFR2, as well as neuropilin-1 and neuropilin-2, whereas PlGF and VEGFB bind only to VEGFR1 and neuropilin-1.
VEGF-C and VEGF-D, which share 23% amino acid sequence identity, are uniquely expressed as preproproteins that contain long N- and C-terminal propeptide extensions around the VEGF homology domain (VHD). The C-terminal amino acid sequenze show a pattern of spacing cysteine residues reminescent of the BR3P sequence. Proteolytic processing of the 354 aa VEGF-D preproprotein creates a secreted proprotein. Further processing by extracellular serine proteases, such as plasmin or furin-like proprotein convertases, forms mature VEGF-D consisting of non-covalently linked homodimers of the 117 aa VHD (Stacker et al., 1999; McColl et al., 2003; McColl et al., 2007). Human VEGF-D is ligand for VEGFR-2 and VEGFR-3.
VEGF-D is expressed in fibroblasts and its messenger is stabilized by cell contacts (Orlandini and Oliviero, 2001). Its receptor VEGFR3 is constitutively expressed in lymphatic endothelial cells and in vascular endothelial cells during angiogenesis and in endothelial precursors and in osteoblasts (Tammela et al., 2011; Orlandini et al., 2006).
VEGF-D and VEGFR-3 are expressed in the osteoblasts of the growing plate. The treatment of primary human osteoblasts with recombinant VEGF-D induces the expression of osteocalcin and the formation of mineralized nodules in a dose-dependent manner (Orlandini et al., 2006).


It is expressed in adult lung, heart, muscle, and small intestine, and is most abundantly expressed in fetal lungs and skin.
VEGF-D expression in mouse fibroblasts is induced by cell interaction mediated by cadherin 11 (Orlandini et al., 2006; Avantaggiato et al., 1998).


Secreted in the extracellular medium.


Growth factor active in angiogenesis, lymphangiogenesis and endothelial cell growth, stimulating their proliferation and migration of blood cells. It may function in the formation of the venous and lymphatic vascular systems during embryogenesis, and also in the maintenance of differentiated lymphatic endothelium in adults. Binds and activates VEGFR-2 (Flk1) and VEGFR-3 (Flt4) receptors.
VEGFD controls the total length and complexity of dendrites both in cultured hippocampal neurons and in the adult mouse hippocampus (Mauceri et al., 2011).
VEGFD together with SDF1α and sFRP1 are major components of stromal cell-derived inducing activity of dopaminergic neurons (Schwartz et al., 2012).


VEGF-D is highly conserved, it shares 94%, 95%, 99%, 97% and 93% aa identity with mouse, rat, equine, canine and bovine VEGF-D, respectively.



Single Nucleotide Polymorphism have been described in mRNA UTR, introns or in exons: see NCBI database.

Implicated in

VEGF-D prognostic marker for tumor growth and dissemination.
High level VEGFD in patients with lymphangioleiomyomatosis.
Serum VEGF-D may be a clinically useful diagnostic test that can distinguish sporadic lymphangioleiomyomatosis from other cystic and chylous lung diseases, potentially decreasing the need for lung biopsy (Young et al., 2008).
Entity name
VEGF-D-dependent regulation of the prostaglandin pathway induces lymphatic vessel dilation and subsequent increase of metastatic spread (Karnezis et al., 2012).
Entity name
Soft tissue sarcoma
VEGF-D significantly increases the migration of sarcoma cells through lymphatic endothelial monolayers. The VEGF-D-dependent induced migration through lymphatics might be the reason for relationship between VEGF-D expression and lymph node metastasis in soft tissue sarcomas (Yanagawa et al., 2012).


Pubmed IDLast YearTitleAuthors
96226381998Embryonic expression pattern of the murine figf gene, a growth factor belonging to platelet-derived growth factor/vascular endothelial growth factor family.Avantaggiato V et al
117786492001VEGF-D is an X-linked/AP-1 regulated putative onco-angiogen in human glioblastoma multiforme.Debinski W et al
86172041996A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases.Joukov V et al
223405922012VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium.Karnezis T et al
217456422011Nuclear calcium-VEGFD signaling controls maintenance of dendrite arborization necessary for memory formation.Mauceri D et al
129636942003Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D.McColl BK et al
172421582007Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2.McColl BK et al
166248152006Vascular endothelial growth factor-D activates VEGFR-3 expressed in osteoblasts inducing their differentiation.Orlandini M et al
94794931998Human FIGF: cloning, gene structure, and mapping to chromosome Xp22.1 between the PIGA and the GRPR genes.Rocchigiani M et al
225354922012Stromal factors SDF1α, sFRP1, and VEGFD induce dopaminergic neuron differentiation of human pluripotent stem cells.Schwartz CM et al
105422481999Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers.Stacker SA et al
219090982011VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling.Tammela T et al
92051221997Molecular cloning of a novel vascular endothelial growth factor, VEGF-D.Yamada Y et al
223264612012Vascular endothelial growth factor-D is a key molecule that enhances lymphatic metastasis of soft tissue sarcomas.Yanagawa T et al
181849702008Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis.Young LR et al

Other Information

Locus ID:

NCBI: 2277
MIM: 300091
HGNC: 3708
Ensembl: ENSG00000165197


dbSNP: 2277
ClinVar: 2277
TCGA: ENSG00000165197


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Focal adhesionKEGGko04510
Cytokine-cytokine receptor interactionKEGGhsa04060
Focal adhesionKEGGhsa04510
Pathways in cancerKEGGhsa05200
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
Response to elevated platelet cytosolic Ca2+REACTOMER-HSA-76005
Platelet degranulationREACTOMER-HSA-114608
Signal TransductionREACTOMER-HSA-162582
Signaling by VEGFREACTOMER-HSA-194138
VEGF ligand-receptor interactionsREACTOMER-HSA-194313
VEGF binds to VEGFR leading to receptor dimerizationREACTOMER-HSA-195399
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
168161212006Functional interaction of VEGF-C and VEGF-D with neuropilin receptors.100
127145622003VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses.85
155906422005The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1.63
197306832009The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.59
129636942003Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D.53
170342942006Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis.47
240978732013Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance).43
172421582007Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2.39
206738682010A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM).36
164670912006Lymphangiogenesis and angiogenesis in bladder cancer: prognostic implications and regulation by vascular endothelial growth factors-A, -C, and -D.32


Marina Rocchigiani ; Salvatore Oliviero

VEGFD (c-fos induced growth factor (vascular endothelial growth factor D))

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

Online version: