The process of angiogenesis is regulated by vascular endothelial growth factor (VEGF) and its 2 known receptor tyrosine kinases FLT1 and KDR/FLK1. The related receptor tyrosine kinase FLT4 is expressed mainly in lymphatic endothelia but does not bind VEGF. Joukov et al. (1996) used affinity chromatography to isolate the ligand of FLT4. They found it to be a polypeptide of 23 kD and named it as VEGFC. Lee et al. (1996) also cloned VEGFC from a human glioma G61 cell cDNA library using a probe based on a sequence from the EST library. Sequence analysis by Joukov et al. (1996) showed that the full-length clones contained an open reading frame of 350 amino acids with a VEGF-homologous region that is 30% identical to VEGF and 27% identical to VEGFB/VRF. The N-terminus contains a putative secretory signal sequence. Transfection assays performed by Joukov et al. (1996) suggested that VEGFC forms disulfide-linked dimers and can activate both the FLT4 and KDR/FLK1 receptor tyrosine kinases. Lee et al. (1996) used competitive binding of purified components to show that VEGFC and FLT4 bind with a high affinity, suggesting that VEGFC is a biologically relevant ligand of FLT4.
NCBI Summary:
The protein encoded by this gene is a member of the platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family. The encoded protein promotes angiogenesis and endothelial cell growth, and can also affect the permeability of blood vessels. The proprotein is further cleaved into a fully processed form that can bind and activate VEGFR-2 and VEGFR-3 receptors. [provided by RefSeq, Apr 2014]
General function
Ligand, Growth factor
Comment
Cellular localization
Secreted
Comment
Ovarian function
Luteinization
Comment
Northern blot hybridization analyses indicated that transcripts of 4.5 and 3.7 kilobases for VEGF, and 1.4 and 2.4 kilobases for VEGF-B and VEGF-C, respectively, are expressed in human granulosa-luteal cells (Laitinen et al. 1997).
Expression regulated by
FSH, LH
Comment
Human granulosa-luteal (GL) cells were treated with hCG, recombinant human FSH, PGE2, as well as
8-bromo-cAMP and 12-O-tetradecanoylphorbol 13-acetate, which activate protein kinase A- and protein kinase C-dependent signaling pathways, respectively. All test agents stimulated the expression of VEGF mRNA levels in a concentration-dependent manner. VEGF-B mRNA levels were not regulated by any of the test agents. However, hCG and 8-bromo-cAMP decreased VEGF-C mRNA levels. In conclusion the mRNAs of VEGF, VEGF-B, and VEGF-C are expressed in human GL cells and their mRNA steady state levels are regulated in cultured human GL cells in an isotype-specific manner (Laitinen et al., 1997).
Ovarian localization
Granulosa, Luteal cells
Comment
Lee et al. (1996) reported that a 2.4-kb VEGF-C (VRP) mRNA is found in several human tissues including adult heart, placenta, ovary, and small intestine and in fetal lung and kidney. Sowter et al. (1997) reported the expression and localization of the vascular endothelial growth factor family including VEGF-C in ovarian epithelial tumors.
Follicle stages
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: embryonic lethal Comment: Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Karkkainen MJ 2003 et al.
Lymphatic vessels are essential for immune surveillance, tissue fluid homeostasis and fat absorption. Defects in lymphatic vessel formation or function cause lymphedema. Here we show that the vascular endothelial growth factor C (VEGF-C) is required for the initial steps in lymphatic development. In Vegfc-/- mice, endothelial cells commit to the lymphatic lineage but do not sprout to form lymph vessels. Sprouting was rescued by VEGF-C and VEGF-D but not by VEGF, indicating VEGF receptor 3 specificity. The lack of lymphatic vessels resulted in prenatal death due to fluid accumulation in tissues, and Vegfc+/- mice developed cutaneous lymphatic hypoplasia and lymphedema. Our results indicate that VEGF-C is the paracrine factor essential for lymphangiogenesis, and show that both Vegfc alleles are required for normal lymphatic development.
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