This page was produced as an assignment for an undergraduate course at Davidson College by Jessica Austin under the supervison of Dr. Campbell

chime image of VEGF, obtained by Y.A.Muller & A.M.De Vos, 8-Apr-97. This file was downloaded from pubmed, a government site

VEGF : Vascular Endothelial Growth Factor

VEGF is classified as a growth factor (or mitogen because it induces mitogenesis). Discovered in 1993, VEGF plays a critical role in embryonic development. In addition to its importance in embryonic development, VEGF is also essential to normal pathological events of Angiogenesis in adults (Gilbert, 2000). VEGF is regulated by the quantity of oxygen in tissues. Tissues not receiving enough oxygen (a situation called hypoxia) obviously need a greater blood supply; therefore the tissues secrete VEGF, which in turn generates the production blood vessels (R&D Systems, 2000).

There are several variations of VEGF; four of them are well known: VEGF 121, VEGF The figure to the left shows receptors for the various forms of VEGF In normal situations transcription factors (hypoxia inducible factor-1a (hif-1a) and -2a) leading to the production of VEGF are degraded by proteosomes in noxia. This means that as long as the cell is receiving enough oxygen transcriptions factors, inducing the production of VEGF, are degraded. Once cells or tissue become starved for oxygen (hypoxia) these transcription factors are stabilized and cease to be degraded (NCBI, 2003). In abnormal situations VEGF can be upregulated in noxia, meaning that VEGF is abundant when there are sufficient quantities of oxygen. Upregulation of VEGF in these situations is most often caused by Oncogenes, which regulate growth factors and are responsible for unchecked cell proliferation (NCBI, 2003).


Characteristics:

165, VEGF 189, and VEGF 206. VEGF ranges in size from 121 amino acids to 206 amino acids (NCBI, 2003). All variations of VEGF are produced from a single gene by a process called alternative splicing. VEGF contains a total of 8 exons, and the protein product of this gene forms a homodimeric structure (see chime image above). The completed protein structure possesses a molecular mass of 45,000, and is extremely specific as to which tissues are susceptible to its influence, namely cells belonging to endothelial tissues. Mutations in VEGF that inhibit it's production are often lethal mutations; embryo's exhibiting this phenotype are terminated and fail to develop.

 

 

R&D Systems, (2000) Vascular Endothelial Growth Factor See Article


ORTHOLOGS OF VASCULAR ENDOTHELIAL GROWTH FACTOR

Homo Sapiens VEGF trams;ated AA Sequence:

MAPMAEGGGQ NHHEVVKFMD VYQRSYCHPI ETLVDIFQEY PDEIEYIFKP SCVPLMRCGG CCNDEGLECV PTEESNITMQ IMRIKPHQGQ HIGEMSFLQH NKCECRPKKD RARQENPCGP CSERRKHLFV QDPQTCKCSC KNTDSRCKAR QLELNERTCR CDKPRR

gene sequence

Rattus norvegicus VEGF translated A.A. Sequence

MNFLLSWVHWTLALLLYLHHAKWSQAAPTTEGEQKAHEVVKFMD
VYQRSYCRPIETLVDIFQEYPDEIEYIFKPSCVPLMRCAGCCNDEALECVPTSESNVT
MQIMRIKPHQSQHIGEMSFLQHSRCECRPKKDRTKPEKKSVRGKGKGQKRKRKKSRFK
SWSVHCEPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR

gene sequence

Mus musculus VEGF translated A.A. Sequence

IETLVDIFQEYPDEIEYIFKPSCVPLMRCAGCCNDEALECVPTS
ESNITMQIMRIKPHQSQHIE

gene sequence

Oryctolagus cuniculus VEGF translated A.A. sequence

LLLYLHHAKWSQAAPMAEEGDNKPHEVVKFMEVYRRSYCQPIET
LVDIFQEYPDEIEYIFKPSCVPLVRCGGCCNDESLECVPTEEFNVTMQIMRIKPHQGQ
HIGEMSFLQHNKCECRPK

gene sequence


APPLICATIONS OF VEGF IN CANCER TREATMENT

Under several specific conditions VEGF can directly contribute to disease states. As mentioned above, Oncogenes provide an alternate method VEGF expression in tissues (Susman 2001). Often upregulation caused by oncogenes leads to unchecked cell proliferation e.g. cancer. Expression of VEGF at the wrong times can lead to growth of solid tumors, hematogenous spread of tumor cell, and growth of metastasis (Susman 2001). Resent scientific investigations have shown that production of VEGF is upregulated in several different types of cancer: breast cancer, prostate cancer, and bladder cancer to name a few. These discoveries lead scientists to the belief that tumors, like every other tissue, must have a blood supply to survive (Fuhrmann, 2000). Tumors provide themselves with a blood supply by upregulating the production of VEGF in their cells through the use of oncogenes. Tumors that are deprived of VEGF do not proliferate. Discovery of VEGF and its importance opened the doors for an alternative treatment for cancer based inhibiting the tumor's access to VEGF, thus denying it a blood source (Fuhrmann, 2000). VEGF inhibitors have been shown reduce the growth rate of tumors, but are unable to totally eradicate the offending cells from the host's body. TSU-68 is a drug used by Japanese Scientists, performing cancer research, as an inhibitor of VEGF (Susman 2001). By itself TSU-68 has been shown to decrease tumor vessel densities, increase apoptosis of endothelial cells, and decrease expression of angiogenic factors (Susman 2001).


APPLICATIONS OF VEGF IN HEART DISEASE

VEGF has recently become important in treating advanced coronary heart disease. Researchers conducted two separate clinical trials, during which they used VEGF cloned into plasmids for gene therapy (Eurekalert, 2003). During surgery, VEGF plasmids are injected directly into the patient’s heart. Scientists believe that VEGF induces the production of new blood vessels in heart tissues starved for oxygen. Participants in clinical trials were limited to those patients with the most severe cases of coronary heart disease (Eurekalert, 2003). Of the thirty patients used in one clinical trial, all but two were alive 18 months after the procedure (Eurekalert, 2003).

See Article