Developmental Signals - Vascular Endothelial Growth Factor

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Introduction

VEGF Receptors[1]

Vascular endothelial growth factor (VEGF) secreted protein growth factor family which stimulates the proliferation of vasular endotheial cells and therefore blood vessel growth.

VEGF is secreted but remains associated with cells or extracellular matrix. It is released by heparin. VEGF belongs to the platelet derive growth factor (PDGF) family, has four isoforms are formed by alternative splicing of the same gene.


Note that in addition to the developmental role this factor has been studied in relation to vascular development in tumours.


Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular

| Blood Vessel Development | Category:VEGF

Some Recent Findings

  • Review - NOTCH regulation of the endothelial cell phenotype[2] "The formation of a hierarchical vascular network is a complex process that requires precise temporal and spatial integration of several signaling pathways. Amongst those, Notch has emerged as a key regulator of multiple steps that expand from endothelial sprouting to arterial specification and remains relevant in the adult."
  • Visceral Endoderm Expression of Yin-Yang1 (YY1) Is Required for VEGFA Maintenance and Yolk Sac Development[3] "Mouse embryos lacking the polycomb group gene member Yin-Yang1 (YY1) die during the peri-implantation stage. To assess the post-gastrulation role of YY1, a conditional knock-out (cKO) strategy was used to delete YY1 from the visceral endoderm of the yolk sac and the definitive endoderm of the embryo. ...these results demonstrate that YY1 is responsible for maintaining VEGF in the developing visceral endoderm and that a VEGF-responsive paracrine signal, originating in the yolk sac mesoderm, is required to promote normal visceral endoderm development."
  • A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development[4] "Vascular endothelial growth factor C (Vegfc) is a secreted protein that guides lymphatic development in vertebrate embryos. However, its role during developmental angiogenesis is not well characterized. Here, we identify a mutation in zebrafish vegfc that severely affects lymphatic development and leads to angiogenesis defects on sensitized genetic backgrounds.... Our results suggest that Vegfc acts in two distinct modes during development: as a paracrine factor secreted from arteries to guide closely associated lymphatic vasculature and as an autocrine factor to drive migratory persistence during angiogenesis."
  • Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting[5]
More recent papers  
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Search term: Vascular Endothelial Growth Factor

<pubmed limit=5>Vascular Endothelial Growth Factor</pubmed>

Human VEGF Family

Table - Human Vegf Family
Approved
Symbol
Approved Name Previous
Symbols
Synonyms Chromosome
PGF placental growth factor PGFL "PLGF, PlGF-2, PlGF, SHGC-10760, D12S1900, PIGF" 14q24.3
VEGFA vascular endothelial growth factor A VEGF "VEGF-A, VPF" 6p21.1
VEGFB vascular endothelial growth factor B VRF VEGFL 11q13.1
VEGFC vascular endothelial growth factor C VRP 4q34.3
VEGFD vascular endothelial growth factor D FIGF VEGF-D Xp22.2
    Links: Developmental Signals - Vascular Endothelial Growth Factor | OMIM Vegf | HGNC | Bmp Family | Fgf Family | Pax Family | Sox Family | Tbx Family | Vegf Family | Wnt Family


Human VEGF Family  
Table - Human Vegf Family
Approved
Symbol
Approved Name Previous
Symbols
Synonyms Chromosome
PGF placental growth factor PGFL "PLGF, PlGF-2, PlGF, SHGC-10760, D12S1900, PIGF" 14q24.3
VEGFA vascular endothelial growth factor A VEGF "VEGF-A, VPF" 6p21.1
VEGFB vascular endothelial growth factor B VRF VEGFL 11q13.1
VEGFC vascular endothelial growth factor C VRP 4q34.3
VEGFD vascular endothelial growth factor D FIGF VEGF-D Xp22.2
    Links: Developmental Signals - Vascular Endothelial Growth Factor | OMIM Vegf | HGNC | Bmp Family | Fgf Family | Pax Family | Sox Family | Tbx Family | Vegf Family | Wnt Family


Structure

Gene

Protein

Vascular endothelial growth factor A

  • Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth.
  • Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels.
  • Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin.

Vascular endothelial growth factor receptor 2

  • Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD.
  • Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis.

Function

Respiration

Lung alveolar type 1 cells express VEGFa required for alveolar angiogenesis.[6]


Links: Respiratory System Development

Signaling Pathway

Arterial Differentiation "Two 2002 papers in Cell and Developmental Cell provide evidence that VEGF directs arterial differentiation. Evidence that sensory nerves direct arteriogenesis (Mukouyama et al., 2002) and that the membrane spanning Notch signaling system is downstream of VEGF (Lawson et al., 2002) emphasize the paracrine regulation of vessel formation."

Model shown in Figure 1. Shh/VEGF/Notch in the Arterial Vasculature Sonic hedgehog (Shh) binding to the receptor complex formed by Patched (Ptc) and Smoothened (Smo) can release the inhibition of Smo by Ptc. The derepressed Smo in turn activates the Gli family of transcription factors. Shh can upregulate the expression of VEGF by mesenchymal cells, but whether the Ptc/Smo/Gli pathway is involved in this Shh-mediated VEGF production is still unclear. VEGF acts on its specific receptors, including Flk-1 and neuropilin-1 (NP-1) and induces arterial-specific EphrinB2 expression on endothelial cells (EC). However, VEGF-induced EphrinB2 expression is dependent on the Notch signaling pathway, and it is unclear (?) if VEGF can activate the Notch pathway in arterial ECs directly. Both the Notch receptor family and their ligand (Delta and Jagged) families are expressed by the EC and smooth muscle cell (SMC)/pericyte in vivo.

(from: Won't You Be My Neighbor? Local Induction of Arteriogenesis Cell, Vol. 110, 289-292, August 9, 2002)

Receptor

Intracellular Signaling

Vascular Endothelial Protein Tyrosine Phosphatase

This phosphatase is involved in vascular development through modulation of a receptor tyrosine kinase (Tie2) activity, the receptor of angiopoietin. Phosphatases remove and kinases add a phosphate group to proteins, phosphorylation is a common intracellular signaling pathway.

Placenta Growth Factor (PlGF)

Name comes from the fact that the gene was cloned from a placenta. See review.[7] Knockout mouse experiments suggest that PIGF is not required for normal vascular development.

  • four protein isoforms, differ in heparin binding
    • PlGF-1 and PlGF-3 - non-heparin binding diffusible isoforms
    • PlGF-2 and PlGF-4 - have heparin binding domains (highly basic 21 amino acids).
Links: OMIM - PGF

OMIM

About OMIM "Online Mendelian Inheritance in Man OMIM is a comprehensive, authoritative, and timely compendium of human genes and genetic phenotypes. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and over 12,000 genes. OMIM focuses on the relationship between phenotype and genotype. It is updated daily, and the entries contain copious links to other genetics resources." OMIM


References

  1. Bussmann J, Bakkers J & Schulte-Merker S. (2007). Early endocardial morphogenesis requires Scl/Tal1. PLoS Genet. , 3, e140. PMID: 17722983 DOI.
  2. Mack JJ & Iruela-Arispe ML. (2018). NOTCH regulation of the endothelial cell phenotype. Curr. Opin. Hematol. , , . PMID: 29547401 DOI.
  3. Rhee S, Guerrero-Zayas MI, Wallingford MC, Ortiz-Pineda P, Mager J & Tremblay KD. (2013). Visceral endoderm expression of Yin-Yang1 (YY1) is required for VEGFA maintenance and yolk sac development. PLoS ONE , 8, e58828. PMID: 23554936 DOI.
  4. Villefranc JA, Nicoli S, Bentley K, Jeltsch M, Zarkada G, Moore JC, Gerhardt H, Alitalo K & Lawson ND. (2013). A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development. Development , 140, 1497-506. PMID: 23462469 DOI.
  5. Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD & Wiegand SJ. (2007). Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc. Natl. Acad. Sci. U.S.A. , 104, 3219-24. PMID: 17296940 DOI.
  6. Yang J, Hernandez BJ, Martinez Alanis D, Narvaez del Pilar O, Vila-Ellis L, Akiyama H, Evans SE, Ostrin EJ & Chen J. (2016). The development and plasticity of alveolar type 1 cells. Development , 143, 54-65. PMID: 26586225 DOI.
  7. De Falco S. (2012). The discovery of placenta growth factor and its biological activity. Exp. Mol. Med. , 44, 1-9. PMID: 22228176 DOI.

Reviews

Articles

Kuypers E, Collins JJ, Jellema RK, Wolfs TG, Kemp MW, Nitsos I, Pillow JJ, Polglase GR, Newnham JP, Germeraad WT, Kallapur SG, Jobe AH & Kramer BW. (2012). Ovine fetal thymus response to lipopolysaccharide-induced chorioamnionitis and antenatal corticosteroids. PLoS ONE , 7, e38257. PMID: 22693607 DOI.

Online Textbooks

  • Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al.New York: Garland Science; 2002.
  • Molecular Cell Biology. 4th edition. Lodish H, Berk A, Zipursky SL, et al.New York: W. H. Freeman; 2000.
  • Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000.

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Cite this page: Hill, M.A. (2019, July 21) Embryology Developmental Signals - Vascular Endothelial Growth Factor. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Vascular_Endothelial_Growth_Factor

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