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UNSW Embryology

Molecular Development Factors - Vascular Endothelial Growth Factor

© Dr Mark Hill (2007)

Acknowledgements

Introduction

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. (More? Heart Notes - Blood Vessels

Page Links: Introduction | Some Recent Findings | Vascular Endothelial Protein Tyrosine Phosphatase | Arterial Differentiation | Database Entry Links | Signaling Factors | WWW Links | References | Glossary

Some Recent Findings

Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci U S A. 2007 Feb 12

"Delta-like ligand (Dll) 4, a transmembrane ligand for the Notch family of receptors, ... Dll4 is induced by VEGF as a negative feedback regulator and acts to prevent overexuberant angiogenic sprouting, promoting the timely formation of a well differentiated vascular network."

Dominguez etal., 2007 Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryonically because of defects in angiogenesis. (Reference yet to be added to Pubmed)

"We confirm that VE-PTP is expressed in endothelium and also show that VE-PTP is highly expressed in the developing outflow tract of the heart and later is expressed in developing heart valves. Vasculogenesis occurs normally in mice lacking VE-PTP; however, angiogenesis is abnormal."

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.

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&endash;292, August 9, 2002)

Database Entry Links

Swiss-Protein NiceProt View

Signaling Factors

Signaling during development, though complex, can also be grouped into a few specific classes. These mechanisms have also been listed and described briefly on Signaling Mechanisms Introduction page.

References

Links: Journals | Online Textbooks | Search Textbooks | PubMed | Search PubMed | Glossary

Journals

Developmental Dynamics

Journal of Neurobiology

Online Textbooks

Molecular Biology of the Cell (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002.

Developmental Biology (6th Edn) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000.

Search NLM Online Textbooks- "hox" : Molecular Biology of the Cell | Molecular Cell Biology | The Cell- A molecular Approach

PubMed

Reviews

Articles

Glossary of Terms

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External WWW Links

Note the dynamic developmental nature of the Internet means that some links may not always work (search using the link term).

Terms

antisense- a sequence of DNA that is complementary usually to coding sequence of DNA or mRNA. Has been used experimentally to perturb or block gene expression. Also a mechanism that has been found to occur naturally as a regulatory mechanism.

autosomal inheritance- some hereditary diseases are described as autosomal which means that the disease is due to a DNA error in one of the 22 pairs that are not sex chromosomes. Both boys and girls can then inherit this error. If the error is in a sex chromosome, the inheritance is said to be sex-linked.

base- another term for nucleotide (usually a t c g).

base pair- Double stranded DNA has nucleotides A-T, C-G, paired by hydrogen bonds (2 for AT, 3 for GC). Note this means that GC is harder to separate that AT.

DNA- DeoxyriboNucleic Acid. The genetic material found in mammalian chromosomes and mitochondria. Consisting of 4 nucleic acids (ATCG) that combine in a triptych (3 nucleotide) code for protein amino acids (3nt=1aa).

DNA duplex- double stranded base-paired DNA forming a helix.

dominant inheritance-With autosomal dominant inheritance, there is an error in one of the 22 chromosome pairs. But the damaged gene dominates over the normal gene received from the other parent. If one of the parents has a disease caused by an autosomal dominant gene, all the children will have a 50 per cent risk of inheriting the dominant gene and a 50 per cent chance of not inheriting it. The children who do not inherit the damaged dominant gene will not themselves suffer from the disease, nor will they be able to pass the gene on to future children. This type of inheritance is present for example in Huntington's disease.

exon- a block of protein encoding sequence of DNA in a gene. Many proteins are made of several exons "stitched" or spliced together by editing out non-coding (intron) sequences.

fasta- a format for listing DNA sequence, where the first line has descritive information followed on the next line by the sequence without numbering.

GC repeat- a string of GC sequence repeated several times. Also associated with GC expansion, a mutational process that may lead eventually to serious gene expression effects.

gene- a sequence of DNA that encodes an individual protein.

genetic code- the 3 nucleotide sequence that forms a codon for a single amino acid or stop. See the gene code.

genome- the complete genetic information in the form of DNA available to a specific species.

hairpin loop- a folding of RNA generated by base pairing making a "===()" structure, the end loop and or stem of this structure can then interact with proteins or other RNA.

intron- a block of DNA within a gene not encoding a protein. Edited, spliced, out during transcription into mRNA. Originally thought not to contain any information, but more and more this appears not to be the case. Some intron sequences have been shown to regulate gene expression during development (eg c elegans, Lin 14)

mRNA- messenger, transcribed from DNA in the nucleus and in mitochondria. Is translated by the ribosome in the cytoplasm (or mitochondrial matrix). Intermediate step in gene expression. (DNA-> mRNA-> protein).

mutation- any process which results in the alteration of the DNA sequence. Some conservative mutations may have no effect on the final amino acid encoded.

point mutation- a change in a single nucleotide.

recessive inheritance-With autosomal recessive inheritance, the diseased individual has inherited the same gene damage from both father and mother. The damage is found on both chromosomes in the pair. But as this is not ´dominant gene damageª, neither father nor mother show any sign of disease, they are healthy carriers of the gene. We are all carriers of about five recessive genes of this type, but as spouses are seldom carriers of exactly the same damaged gene(s), all will probably go well in the next generation.

ribosome- complex of rRNA and ribosomal proteins, bind mRNA and translate it into protein.

RNA- RiboNucleic Acid. The intermediate nucleic acid involved in gene expression. It comes in 3 forms: tRNA, mRNA, rRNA.

rRNA- ribosomal, translates mRNA into protein. rRNA provides the "scaffolding" on which many ribosomal proteins are assembled as 2 subunits that themselves assemble to form a ribosome. rRNA genes are localized to the nucleolus in the nucleus, a sometimes visible region of DNA usually constantly being transcribed.

telomere- regions at the end of chromosomes. Shortening of the telomeres is thought to be associated with cellular aging. The enzyme that maintains the telomere is called telomerase. Introducing this gene into a cell can extend the cells lifespan.

transcription factor- a protein which binds to DNA activating (usually) gene expression. There are many different ways and forms that this activation can take place, but most transcription factors fall into specific classes (eg zinc fingers, helix loop helix).

tRNA- transfer, binds single amino acids acts as a "donor' for protein synthesis.

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