View source for Vascular endothelial growth factor

{{Short description|Protein involved in blood vessel growth}}
{{Distinguish|epidermal growth factor}}
{{Use dmy dates|date=January 2018}}
'''Vascular endothelial growth factor''' ('''VEGF''', {{IPAc-en|v|ɛ|dʒ|'|ɛ|f}}), originally known as '''vascular permeability factor''' ('''VPF'''),<ref name="Senger1">{{cite journal |last1=Senger |first1=D. |last2=Galli |first2=S. |last3=Dvorak |first3=A. |last4=Perruzzi |first4=C. |last5=Harvey |first5=V. |last6=Dvorak |first6=H. |title=Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid |journal=Science |date=25 February 1983 |volume=219 |issue=4587 |pages=983–985 |doi=10.1126/science.6823562 |pmid=6823562 |bibcode=1983Sci...219..983S }}</ref> is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of [[growth factors]], the [[platelet-derived growth factor]] family of [[Cystine knot|cystine-knot]] growth factors. They are important signaling [[protein]]s involved in both [[vasculogenesis]] (the ''[[De novo synthesis|de novo]]'' formation of the embryonic [[circulatory system]]) and [[angiogenesis]] (the growth of blood vessels from pre-existing vasculature).

It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate such as in hypoxic conditions.<ref>{{cite journal | last1 = Palmer | first1 = Biff F. | last2 = Clegg | first2 = Deborah J. | year = 2014 | title = Oxygen sensing and metabolic homeostasis | doi = 10.1016/j.mce.2014.08.001 | pmid = 25132648 | journal = Molecular and Cellular Endocrinology | volume = 397| issue = 1–2| pages = 51–57 | s2cid = 5165215 }}</ref> Serum concentration of VEGF is high in [[bronchial asthma]] and [[diabetes mellitus]].<ref>{{cite journal |last1=Cooper |first1=Mark |first2=Dimitria |last2=Vranes |first3=Sherif |last3=Youssef |first4=Steven A. |last4=Stacker |first5=Alison J. |last5=Cox |first6=Bishoy |last6=Rizkalla |first7=David J. |last7=Casley |first8=Leon A. |last8=Bach |first9=Darren J. |last9=Kelly |first10=Richard E. |last10=Gilbert |title=Increased Renal Expression of Vascular Endothelial Growth Factor (VEGF) and Its Receptor VEGFR-2 in Experimental Diabetes |journal=Diabetes |date=November 1999 |volume=48 |issue=11 |pages=2229–2239 |doi=10.2337/diabetes.48.11.2229 |pmid=10535459 }}</ref>
VEGF's normal function is to create new blood vessels during [[embryonic development]], new blood vessels after injury, muscle following exercise, and new vessels ([[collateral circulation]]) to bypass blocked vessels.
It can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express VEGF are able to grow and metastasize. Overexpression of VEGF can cause vascular disease in the [[retina]] of the eye and other parts of the body. Drugs such as [[aflibercept]], [[bevacizumab]], [[ranibizumab]], and [[pegaptanib]] can inhibit VEGF and control or slow those diseases.

==History==
In 1970, [[Judah Folkman]] ''et al''. described a factor secreted by tumors causing angiogenesis and called it ''tumor angiogenesis factor''.<ref>{{Cite journal|last=Folkman|first=J|date=1 February 1971|title=Isolation of a tumor factor responsible for angiogenesis|journal=Journal of Experimental Medicine|volume=133|issue=2|pages=275–288|doi=10.1084/jem.133.2.275|pmid=4332371|pmc=2138906}}</ref> In 1983  Senger ''et al.'' identified a ''vascular permeability factor'' secreted by tumors in guinea pigs and hamsters.<ref name="Senger1" /> In 1989 Ferrara and Henzel described an identical factor in bovine pituitary follicular cells which they purified, cloned and named VEGF.<ref>{{cite journal |last1=Ferrara |first1=N |last2=Henzel |first2=WJ |title=Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells |journal=Biochemical and Biophysical Research Communications |date=15 June 1989 |volume=161 |issue=2 |pages=851–858 |doi=10.1016/0006-291x(89)92678-8 |pmid=2735925 }}</ref> A similar VEGF alternative splicing was discovered by Tischer ''et al.'' in 1991.<ref>{{cite journal |last1=Tischer |first1=E |last2=Mitchell |first2=R |last3=Hartman |first3=T |last4=Silva |first4=M |last5=Gospodarowicz |first5=D |last6=Fiddes |first6=JC |last7=Abraham |first7=JA |title=The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing |journal=The Journal of Biological Chemistry |date=25 June 1991 |volume=266 |issue=18 |pages=11947–54 |doi=10.1016/S0021-9258(18)99049-6 |pmid=1711045 |doi-access=free }}</ref> Between 1996 and 1997, Christinger and De Vos obtained the crystal structure of VEGF, first at 2.5 Å resolution and later at 1.9 Å.<ref>{{cite journal|last1=Christinger|first1=Hans W.|last2=Muller|first2=Yves A.|last3=Berleau|first3=Lea T.|last4=Keyt|first4=Bruce A.|last5=Cunningham|first5=Brian C.|last6=Ferrara|first6=Napoleone|last7=de Vos|first7=Abraham M.|title=Crystallization of the receptor binding domain of vascular endothelial growth factor|journal=Proteins: Structure, Function, and Genetics|date=November 1996|volume=26|issue=3|pages=353–357|doi=10.1002/(SICI)1097-0134(199611)26:3<353::AID-PROT9>3.0.CO;2-E|pmid=8953654|s2cid=35946525 }}</ref><ref>{{cite journal |last1=Muller |first1=Yves A. |last2=Li |first2=Bing |last3=Christinger |first3=Hans W. |last4=Wells |first4=James A. |last5=Cunningham |first5=Brian C. |last6=Vos |first6=Abraham M. de |title=Vascular endothelial growth factor: Crystal structure and functional mapping of the kinase domain receptor binding site |journal=Proceedings of the National Academy of Sciences |date=8 July 1997 |volume=94 |issue=14 |pages=7192–7197 |doi=10.1073/pnas.94.14.7192 |pmid=9207067 |pmc=23789 |bibcode=1997PNAS...94.7192M |doi-access=free }}</ref><ref>{{cite journal |last1=Muller |first1=Yves A |last2=Christinger |first2=Hans W |last3=Keyt |first3=Bruce A |last4=de Vos |first4=Abraham M |title=The crystal structure of vascular endothelial growth factor (VEGF) refined to 1.93 Å resolution: multiple copy flexibility and receptor binding |journal=Structure |date=October 1997 |volume=5 |issue=10 |pages=1325–1338 |doi=10.1016/s0969-2126(97)00284-0 |pmid=9351807 |doi-access=free }}</ref>

[[FLT1|Fms-like tyrosine kinase-1]] (flt-1) was shown to be a VEGF receptor by Ferrara ''et al.'' in 1992.<ref>{{cite journal |last1=Vries |first1=C. de |last2=Escobedo |first2=J. A. |last3=Ueno |first3=H. |last4=Houck |first4=K. |last5=Ferrara |first5=N. |last6=Williams |first6=L. T. |title=The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor |journal=Science |date=21 February 1992 |volume=255 |issue=5047 |pages=989–991 |doi=10.1126/science.1312256 |pmid=1312256 |bibcode=1992Sci...255..989D }}</ref> The [[kinase insert domain receptor]] (KDR) was shown to be a VEGF receptor by Terman ''et al.'' in 1992 as well.<ref>{{cite journal |last1=Terman |first1=Bruce I. |last2=Dougher-Vermazen |first2=Maureen |last3=Carrion |first3=Miguel E. |last4=Dimitrov |first4=Dragan |last5=Armellino |first5=Douglas C. |last6=Gospodarowicz |first6=Denis |last7=Böhlen |first7=Peter |title=Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor |journal=Biochemical and Biophysical Research Communications |date=30 September 1992 |volume=187 |issue=3 |pages=1579–1586 |doi=10.1016/0006-291x(92)90483-2 |pmid=1417831 |doi-access=free }}</ref> In 1998, [[neuropilin 1]] and [[neuropilin 2]] were shown to act as VEGF receptors.<ref name="Neuropilin-1 Is Expressed by Endoth">{{cite journal |last1=Soker |first1=Shay |last2=Takashima |first2=Seiji |last3=Miao |first3=Hua Quan |last4=Neufeld |first4=Gera |last5=Klagsbrun |first5=Michael |title=Neuropilin-1 Is Expressed by Endothelial and Tumor Cells as an Isoform-Specific Receptor for Vascular Endothelial Growth Factor |journal=Cell |date=March 1998 |volume=92 |issue=6 |pages=735–745 |doi=10.1016/s0092-8674(00)81402-6 |pmid=9529250 |s2cid=547080 |doi-access=free }}</ref>

==Classification==
[[Image:VEGF Vammin.png|250px|right|thumb|Crystal structure of [[Vammin]], a [[VEGF-F]] from a snake venom]]
In mammals, the VEGF family comprises five members: [[VEGF-A]], placenta growth factor ([[Placental growth factor|PGF]]), [[VEGF-B]], [[VEGF-C]] and [[VEGF-D]]. The latter members were discovered after VEGF-A; before their discovery, VEGF-A was known as VEGF. A number of VEGF-related proteins encoded by viruses ([[VEGF-E]]) and in the venom of some snakes ([[VEGF-F]]) have also been discovered.

{|class="wikitable"
|+VEGF family
|-
! Type !! Function
|-
! [[VEGF-A]]
|
* [[Angiogenesis]] {{Citation needed|date=April 2017}}
** ↑ [[cell migration|Migration]] of [[endothelial cell]]s
** ↑ [[mitosis]] of [[endothelial cell]]s
** ↑ [[Matrix metalloproteinase]] activity
** ↑ [[αvβ3]] activity
** ↑ [[cell migration|Migration]] and [[Cell proliferation|proliferation]] of [[Astrocyte]]s <ref>{{cite journal |last1=Bang |first1=Seokyoung |last2=Lee|first2=Seung-Ryeol |last3=Ko |first3=Jihoon |last4=Son |first4=Kyungmin |last5=Tahk |first5=Dongha |last6=Ahn |first6=Jungho |last7=Im |first7=Changkyun |last8=LiJeon |first8=Noo |title=A Low Permeability Microfluidic Blood-Brain Barrier Platform with Direct Contact between Perfusable Vascular Network and Astrocytest |journal=Scientific Reports |date=14 August 2017 |volume=7 |issue=1 |page=8083 |doi=10.1038/s41598-017-07416-0 |pmid=28808270|pmc=5556097 |bibcode=2017NatSR...7.8083B }}</ref> 
** creation of blood vessel [[Lumen (anatomy)|lumen]]
** creates [[vessel fenestrations|fenestrations]]
*[[Chemotactic]] for [[macrophages]]<ref>{{cite journal|journal=Adipocyte|title=New insights into adipose tissue VEGF-A actions in the control of obesity and insulin resistance|volume=2|issue=2|date=1 April 2013|doi=10.4161/adip.22880|doi-access=free|author1=Ivet Elias|author2=Sylvie Franckhauser|author3=Fatima Bosch|pages=109–112|pmid=23805408 |pmc=3661112 }}</ref> and [[granulocytes]] {{Citation needed|date=April 2017}}
* [[Vasodilation]] (indirectly by [[nitric oxide|NO]] release) {{Citation needed|date=April 2017}}
* [[Lymphangiogenesis]]<ref>{{cite journal |last1=Cursiefen |first1=Claus |last2=Chen |first2=Lu |last3=Borges |first3=Leonardo P. |last4=Jackson |first4=David |last5=Cao |first5=Jingtai |last6=Radziejewski |first6=Czeslaw |last7=D’Amore |first7=Patricia A. |last8=Dana |first8=M. Reza |last9=Wiegand |first9=Stanley J. |last10=Streilein |first10=J. Wayne |title=VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment |journal=Journal of Clinical Investigation |date=1 April 2004 |volume=113 |issue=7 |pages=1040–1050 |doi=10.1172/JCI200420465 |pmid=15057311 |pmc=379325 }}</ref>
|-
! [[VEGF-B]]
| Embryonic angiogenesis (myocardial tissue, to be specific)<ref>{{cite journal|last=Claesson-Welsh|first=L.|title=VEGF-B Taken to Our Hearts: Specific Effect of VEGF-B in Myocardial Ischemia|journal=Arteriosclerosis, Thrombosis, and Vascular Biology|date=20 August 2008|volume=28|issue=9|pages=1575–1576|doi=10.1161/ATVBAHA.108.170878|pmid=18716319|doi-access=}}</ref>
|-
! [[VEGF-C]]
| [[Lymphangiogenesis]]<ref>{{cite journal|url=https://www.embopress.org/doi/full/10.1093/emboj/20.4.672|doi=10.1093/emboj/20.4.672|doi-access=free|accessdate=3 February 2022|title=Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis|journal=[[The EMBO Journal]]|date=15 February 2001|issue=4|volume=20|last1=Mandriota|first1=S. J.|last2=Jussila|first2=L.|last3=Jeltsch|first3=M.|last4=Compagni|first4=A.|last5=Baetens|first5=D.|last6=Prevo|first6=R.|last7=Banerji|first7=S.|last8=Huarte|first8=J.|last9=Montesano|first9=R.|last10=Jackson|first10=D. G.|last11=Orci|first11=L.|last12=Alitalo|first12=K.|last13=Christofori|first13=G.|last14=Pepper|first14=M. S.|pages=672–682|pmid=11179212|pmc=145430}}</ref>
|-
! [[VEGF-D]]
| Needed for the development of [[lymphatic vasculature]] surrounding lung bronchioles {{Citation needed|date=April 2017}}
|-
! [[PlGF]]
| Important for Vasculogenesis, Also needed for angiogenesis during ischemia, inflammation, wound healing, and cancer. {{Citation needed|date=April 2017}}
|-
|}

Activity of VEGF-A, as its name implies, has been studied mostly on cells of the vascular [[endothelium]], although it does have effects on a number of other cell types (e.g., stimulation [[monocyte]]/[[macrophage]] migration, neurons, cancer cells, kidney epithelial cells). In vitro, VEGF-A has been shown to stimulate endothelial cell [[mitogenesis]] and [[cell migration]]. VEGF-A is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.

==Isoforms==
[[Image:VEGF isoforms.png|250px|right|thumb|Schematic representation of the different isoforms of human VEGF]]
There are multiple isoforms of VEGF-A that result from [[alternative splicing]] of [[mRNA]] from a single, 8-[[exon]] ''VEGFA'' gene. These are classified into two groups which are referred to according to their terminal exon (exon 8) splice site: the proximal splice site (denoted VEGF<sub>xxx</sub>) or distal splice site (VEGF<sub>xxx</sub>b). In addition, alternate splicing of exon 6 and 7 alters their [[heparin]]-binding affinity and amino acid number (in humans: VEGF<sub>121</sub>, VEGF<sub>121</sub>b, VEGF<sub>145</sub>, VEGF<sub>165</sub>, VEGF<sub>165</sub>b, VEGF<sub>189</sub>, VEGF<sub>206</sub>; the rodent orthologs of these proteins contain one fewer amino acids). These domains have important functional consequences for the VEGF splice variants, as the terminal (exon 8) splice site determines whether the proteins are pro-angiogenic (proximal splice site, expressed during angiogenesis) or anti-angiogenic (distal splice site, expressed in normal tissues). In addition, inclusion or exclusion of exons 6 and 7 mediate interactions with [[heparan sulfate]] [[proteoglycans]] (HSPGs) and [[neuropilin]] co-receptors on the cell surface, enhancing their ability to bind and activate the [[VEGF receptors]] (VEGFRs).<ref>{{cite journal |last1=Cébe Suarez |first1=S. |last2=Pieren |first2=M. |last3=Cariolato |first3=L. |last4=Arn |first4=S. |last5=Hoffmann |first5=U. |last6=Bogucki |first6=A. |last7=Manlius |first7=C. |last8=Wood |first8=J. |last9=Ballmer-Hofer |first9=K. |title=A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2 |journal=Cellular and Molecular Life Sciences |date=September 2006 |volume=63 |issue=17 |pages=2067–2077 |doi=10.1007/s00018-006-6254-9 |pmid=16909199 |s2cid=28267679 |url=https://www.dora.lib4ri.ch/psi/islandora/object/psi%3A32547 |pmc=11136335 }}</ref> Recently, VEGF-C has been shown to be an important inducer of neurogenesis in the murine subventricular zone, without exerting angiogenic effects.<ref>{{cite journal | last1 = Shin | first1 = Y. J. | last2 = Choi | first2 = J. S. |display-authors=etal | year = 2010 | title = Induction of vascular endothelial growth factor receptor-3 mRNA in glial cells following focal cerebral ischemia in rats | journal = J Neuroimmunol | volume = 229 | issue = 1–2| pages = 81–90 | doi=10.1016/j.jneuroim.2010.07.008| pmid = 20692049 | s2cid = 21073290 }}</ref>

==Mechanism==
[[Image:VEGF receptors.png|thumb|right|200px|Types of VEGF and their [[VEGF receptors]].<ref>{{cite journal |last1=Häggström |first1=Mikael |title=Medical gallery of Mikael Häggström 2014 |journal=WikiJournal of Medicine |date=2014 |volume=1 |issue=2 |doi=10.15347/wjm/2014.008 |doi-access=free }}</ref>{{self-published inline|date=January 2021}}]]
All members of the VEGF family stimulate cellular responses by binding to [[tyrosine kinase]] receptors (the [[VEGFRs]]) on the cell surface, causing them to dimerize and become activated through [[transphosphorylation]], although to different sites, times, and extents. The VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region, and an intracellular portion containing a split [[tyrosine-kinase]] domain. VEGF-A binds to VEGFR-1 ([[Flt-1]]) and VEGFR-2 ([[KDR/Flk-1]]).<ref name="pmid17658244">{{cite journal |last1=Holmes |first1=Katherine |last2=Roberts |first2=Owain Ll |last3=Thomas |first3=Angharad M. |last4=Cross |first4=Michael J. |title=Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition |journal=Cellular Signalling |volume=19 |issue=10 |pages=2003–12 |year=2007 |pmid=17658244 |doi=10.1016/j.cellsig.2007.05.013}}</ref> VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well-defined, although it is thought to modulate VEGFR-2 signaling.<ref>{{cite journal |last1=Karkkainen |first1=M.J. |last2=Petrova |first2=T.V. |title=Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis |journal=Oncogene |volume=19 |pages=5598–5605 |year=2000|pmid=11114740 |issue=49 |doi=10.1038/sj.onc.1203855 |doi-access= |s2cid=2374117 }}</ref> Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). VEGF-C and VEGF-D, but not VEGF-A, are ligands for a third receptor ([[FLT4|VEGFR-3/Flt4]]), which mediates [[lymphangiogenesis]]. The receptor (VEGFR3) is the site of binding of main ligands (VEGFC and VEGFD), which mediates perpetual action and function of ligands on
target cells. Vascular endothelial growth factor-C can stimulate lymphangiogenesis (via VEGFR3) and angiogenesis via VEGFR2. Vascular endothelial growth factor-R3 has been detected in lymphatic endothelial cells in CL of many species, cattle, buffalo and primate.<ref>{{cite journal | last1 = Ali | first1 = Ibne |display-authors=etal| year = 2013 | title = Expression and localization of locally produced growth factors regulating lymphangiogenesis during different stages of the estrous cycle in corpus luteum of buffalo" (Bubalus bubalis) | journal = Theriogenology | volume =  81| issue = 3| pages = 428–436| doi=10.1016/j.theriogenology.2013.10.017| pmid = 24246422 }}</ref>

In addition to binding to [[VEGF receptors|VEGFRs]], VEGF binds to receptor complexes consisting of both [[neuropilin]]s and VEGFRs. This receptor complex has increased VEGF signalling activity in [[Endothelium|endothelial]] cells ([[blood vessel]]s).<ref name="Neuropilin-1 Is Expressed by Endoth"/><ref>{{cite journal |last1=Herzog |first1=Birger |last2=Pellet-Many |first2=Caroline |last3=Britton |first3=Gary |last4=Hartzoulakis |first4=Basil |last5=Zachary |first5=Ian C. |title=VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation |journal=Molecular Biology of the Cell |date=8 June 2011 |volume=22 |issue=15 |pages=2766–2776 |doi=10.1091/mbc.E09-12-1061 |pmid=21653826 |pmc=3145551 }}</ref> Neuropilins (NRP) are [[Pleiotropy|pleiotropic]] receptors and therefore other molecules may interfere with the signalling of the NRP/VEGFR receptor complexes. For example, Class 3 [[semaphorin]]s compete with VEGF<sub>165</sub> for NRP binding and could therefore regulate VEGF-mediated [[angiogenesis]].<ref name=pmid25386118>{{cite journal |last1=Mecollari |first1=Vasil |last2=Nieuwenhuis |first2=Bart |last3=Verhaagen |first3=Joost |title=A perspective on the role of class III semaphorin signaling in central nervous system trauma |journal=Frontiers in Cellular Neuroscience |date=27 October 2014 |volume=8 |page=328 |doi=10.3389/fncel.2014.00328 |pmid=25386118 |pmc=4209881 |doi-access=free }}</ref>

==Expression==
VEGF-A production can be induced in a cell that is not receiving enough [[oxygen]].<ref name="pmid17658244" /> When a cell is deficient in oxygen, it produces HIF, [[hypoxia-inducible factor]], a transcription factor. HIF stimulates the release of VEGF-A, among other functions (including modulation of erythropoiesis). Circulating VEGF-A then binds to VEGF receptors on endothelial cells, triggering a [[tyrosine kinase]] pathway leading to angiogenesis.{{clarify|date=June 2018}} The expression of [[angiopoietin-2]] in the absence of VEGF leads to endothelial cell death and vascular regression.<ref>{{cite book | last = Harmey | first = Judith | title = VEGF and cancer | publisher = Landes Bioscience/Eurekah.com New York, N.Y. Kluwer Academic/Plenum Publishers | location = Georgetown, Tex | year = 2004 | isbn = 978-0-306-47988-5 }}{{page needed|date=January 2021}}</ref> Conversely, a German study done ''[[in vivo]]'' found that VEGF concentrations actually decreased after a 25% reduction in oxygen intake for 30 minutes.<ref name="pmid16219663">{{cite journal |last1=Oltmanns |first1=Kerstin M. |last2=Gehring |first2=Hartmut |last3=Rudolf |first3=Sebastian |last4=Schultes |first4=Bernd |last5=Hackenberg |first5=Claudia |last6=Schweiger |first6=Ulrich |last7=Born |first7=Jan |last8=Fehm |first8=Horst L. |last9=Peters |first9=Achim |title=Acute hypoxia decreases plasma VEGF concentration in healthy humans |journal=American Journal of Physiology. Endocrinology and Metabolism |date=1 March 2006 |volume=290 |issue=3 |pages=E434–E439 |doi=10.1152/ajpendo.00508.2004 |pmid=16219663 |s2cid=32679788 }}</ref> HIF1 alpha and HIF1 beta are constantly being produced but HIF1 alpha is highly O<sub>2</sub> labile, so, in aerobic conditions, it is degraded. When the cell becomes hypoxic, HIF1 alpha persists and the HIF1alpha/beta complex stimulates VEGF release. the combined use of microvesicles and 5-FU resulted in enhanced chemosensitivity of squamous cell carcinoma cells more than the use of either 5-FU or microvesicle alone. In addition, down regulation of VEGF gene expression was associated with decreased CD1 gene expression.<ref>{{cite journal |last1=Abd El Latif |first1=Ghada |last2=Aboushady |first2=Iman |last3=Sabry |first3=Dina |title=Decreased VEGF and Cyclin D1 Genes Expression Enhances Chemosensitivity of Human Squamous Cell Carcinoma Cells to 5-Fluorouracil and/or Mesenchymal Stem Cells-Derived Microvesicles |journal=Egyptian Dental Journal |date=1 April 2019 |volume=65 |issue=2 |pages=1217–1228 |doi=10.21608/EDJ.2019.72197 |doi-access=free }}</ref>

==Clinical significance==
{{see also|Anti vascular endothelial growth factor therapy|Neurobiological effects of physical exercise#VEGF signaling}}

===In disease===

VEGF-A and the corresponding receptors are rapidly up-regulated after traumatic injury of the [[central nervous system]] (CNS). VEGF-A is highly expressed in the acute and sub-acute stages of CNS injury, but the protein expression declines over time. This time-span of VEGF-A expression corresponds with the endogenous [[Revascularization|re-vascularization]] capacity after injury.<ref name=pmid25386118/> This would suggest that VEGF-A / VEGF<sub>165</sub> could be used as target to promote angiogenesis after traumatic CNS injuries. However, there are contradicting scientific reports about the effects of VEGF-A treatments in CNS injury models.<ref name=pmid25386118/>

Although it has not been associated as a [[Biomarkers in Medicine|biomarker]] for the diagnosis of acute ischemic [[stroke]],<ref>{{cite journal |last1=Seidkhani-Nahal |first1=Ali |last2=Khosravi |first2=Afra |last3=Mirzaei |first3=Asad |last4=Basati |first4=Gholam |last5=Abbasi |first5=Milad |last6=Noori-Zadeh |first6=Ali |title=Serum vascular endothelial growth factor (VEGF) levels in ischemic stroke patients: a systematic review and meta-analysis of case–control studies |journal=Neurological Sciences |date=5 September 2020 |volume=42 |issue=5 |pages=1811–1820 |doi=10.1007/s10072-020-04698-7 |pmid=32888077 |s2cid=221494935 }}</ref> high levels of serum VEGF in the first 48 hours after an cerebral infarct have been associated with a poor prognosis after 6 months<ref>{{cite journal |last1=Escudero |first1=Carlos |last2=Acurio |first2=Jesenia |last3=López |first3=Eduardo |last4=Rodríguez |first4=Andrés |last5=Benavente |first5=Antonia |last6=Lara |first6=Evelyn |last7=Korzeniewski |first7=Steven J. |title=Vascular endothelial growth factor and poor prognosis after ischaemic stroke |journal=European Journal of Neurology |year=2020 |volume=28 |issue=5 |pages=1759–1764 |doi=10.1111/ene.14641 |pmid=33176035 |s2cid=226310802 }}</ref> and 2 years.<ref>{{cite journal |last1=Åberg |first1=N. David |last2=Wall |first2=Alexander |last3=Anger |first3=Olof |last4=Jood |first4=Katarina |last5=Andreasson |first5=Ulf |last6=Blennow |first6=Kaj |last7=Zetterberg |first7=Henrik |last8=Isgaard |first8=Jörgen |last9=Jern |first9=Christina |last10=Svensson |first10=Johan |title=Circulating levels of vascular endothelial growth factor and post-stroke long-term functional outcome |journal=Acta Neurologica Scandinavica |date=May 2020 |volume=141 |issue=5 |pages=405–414 |doi=10.1111/ane.13219 |pmid=31919840 |doi-access=free }}</ref>

VEGF-A has been implicated with poor prognosis in [[breast cancer]]. Numerous studies show a decreased overall survival and disease-free survival in those tumors overexpressing VEGF. The overexpression of VEGF-A may be an early step in the process of [[metastasis]], a step that is involved in the "angiogenic" switch. Although VEGF-A has been correlated with poor survival, its exact mechanism of action in the progression of tumors remains unclear.<ref>{{Cite journal |last1=Mohammed |first1=R. a. A. |last2=Green |first2=A. |last3=El-Shikh |first3=S. |last4=Paish |first4=E. C. |last5=Ellis |first5=I. O. |last6=Martin |first6=S. G. |date=April 2007 |title=Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis |journal=British Journal of Cancer |language=en |volume=96 |issue=7 |pages=1092–1100 |doi=10.1038/sj.bjc.6603678 |pmid=17353919 |issn=1532-1827|doi-access=free |pmc=2360132 }}</ref>

VEGF-A is also released in [[rheumatoid arthritis]] in response to [[TNF-α]], increasing endothelial permeability and swelling and also stimulating angiogenesis (formation of capillaries).<ref>{{Cite journal |last=Taylor |first=Peter C. |date=2002 |title=VEGF and imaging of vessels in rheumatoid arthritis |journal=Arthritis Research |volume=4 |issue=Suppl 3 |pages=S99–107 |doi=10.1186/ar582 |issn=1465-9905 |pmc=3240157 |pmid=12110128 |doi-access=free }}</ref>

VEGF-A is also important in [[diabetic retinopathy]] (DR). The microcirculatory problems in the retina of people with [[diabetes]] can cause retinal ischaemia, which results in the release of VEGF-A, and a switch in the balance of pro-angiogenic VEGF<sub>xxx</sub> isoforms over the normally expressed VEGF<sub>xxx</sub>b isoforms. VEGF<sub>xxx</sub> may then cause the creation of new blood vessels in the retina and elsewhere in the eye, heralding changes that may threaten the sight.

VEGF-A plays a role in the disease pathology of the wet form [[age-related macular degeneration]] (AMD), which is the leading cause of blindness for the elderly of the industrialized world. The vascular pathology of AMD shares certain similarities with diabetic retinopathy, although the cause of disease and the typical source of neovascularization differs between the two diseases.

VEGF-D serum levels are significantly elevated in patients with [[Hemangiosarcoma|angiosarcoma]].<ref name="pmid14746640">{{cite journal |last1=Amo |first1=Y. |last2=Masuzawa |first2=M. |last3=Hamada |first3=Y. |last4=Katsuoka |first4=K. |title=Serum concentrations of vascular endothelial growth factor-D in angiosarcoma patients |journal=British Journal of Dermatology |volume=150 |issue=1 |pages=160–1 |year=2004 |pmid=14746640 |doi=10.1111/j.1365-2133.2004.05751.x|s2cid=38291933 }}</ref>

Once released, VEGF-A may elicit several responses. It may cause a [[cell (biology)|cell]] to survive, move, or further differentiate. Hence, VEGF is a potential target for the treatment of [[cancer]]. The first anti-VEGF drug, a [[monoclonal antibody]] named [[bevacizumab]], was approved in 2004. Approximately 10–15% of patients benefit from bevacizumab therapy; however, biomarkers for bevacizumab efficacy are not yet known.

Current studies show that VEGFs are not the only promoters of angiogenesis. In particular, [[FGF2]] and HGF are potent angiogenic factors.

Patients suffering from pulmonary emphysema have been found to have decreased levels of VEGF in the pulmonary arteries.

VEGF-D has also been shown to be over expressed in [[lymphangioleiomyomatosis]] and is currently used as a diagnostic biomarker in the treatment of this rare disease.<ref>{{cite journal |last1=Young |first1=Lisa R. |last2=Inoue |first2=Yoshikazu |last3=McCormack |first3=Francis X. |title=Diagnostic Potential of Serum VEGF-D for Lymphangioleiomyomatosis |journal=New England Journal of Medicine |date=10 January 2008 |volume=358 |issue=2 |pages=199–200 |doi=10.1056/NEJMc0707517 |pmid=18184970 |pmc=3804557 }}</ref>

In the [[kidney]], increased expression of VEGF-A in [[Glomerulus (kidney)|glomeruli]] directly causes the glomerular hypertrophy that is associated with proteinuria.<ref>{{cite journal |last1=Liu |first1=E. |last2=Morimoto |first2=M. |last3=Kitajima |first3=S. |last4=Koike |first4=T. |last5=Yu |first5=Y. |last6=Shiiki |first6=H. |last7=Nagata |first7=M. |last8=Watanabe |first8=T. |last9=Fan |first9=J. |title=Increased Expression of Vascular Endothelial Growth Factor in Kidney Leads to Progressive Impairment of Glomerular Functions |journal=Journal of the American Society of Nephrology |volume=18 |issue=7 |pages=2094–104 |year=2007 |pmid=17554151 |doi=10.1681/ASN.2006010075 |doi-access=free }}</ref>

VEGF alterations can be predictive of early-onset [[pre-eclampsia]].<ref>{{Cite journal | last1 = Andraweera | first1 = P. H. | last2 = Dekker | first2 = G. A. | last3 = Roberts | first3 = C. T. | doi = 10.1093/humupd/dms011 | title = The vascular endothelial growth factor family in adverse pregnancy outcomes | journal = Human Reproduction Update | volume = 18 | issue = 4 | pages = 436–457 | year = 2012 | pmid =  22495259| doi-access = free }}</ref>

[[Gene therapy|Gene therapies]] for refractory angina establish expression of VEGF in epicardial cells to promote angiogenesis.<ref>{{Cite web|url=https://genomecontext.com/gene-therapy-for-refractory-angina/|title=Gene therapy for refractory angina|date=16 October 2019|website=Genome Context|language=en-US|access-date=2019-10-16|archive-date=16 October 2019|archive-url=https://web.archive.org/web/20191016135641/https://genomecontext.com/gene-therapy-for-refractory-angina/|url-status=dead}}</ref>

==See also==
* [[Proteases in angiogenesis]]
* [[Withaferin A]], a potent inhibitor of angiogenesis

== References ==
{{Reflist}}

==Further reading==
{{refbegin | 2}}
*{{cite journal  |vauthors=Bengoetxea H, Argandoña EG, Lafuente JV |title=Effects of Visual Experience on Vascular Endothelial Growth Factor Expression during the Postnatal Development of the Rat Visual Cortex |journal=Cerebral Cortex |volume=18 |issue= 7 |pages= 1630–39 |year= 2008 |pmid= 17986606 |doi=10.1093/cercor/bhm190  | pmc=2430152}}
*{{cite journal  |vauthors=Zan L, Wu H, Jiang J, Zhao S, Song Y, Teng G, Li H, Jia Y, Zhou M, Zhang X, Qi J, Wang J |title=Temporal profile of Src, SSeCKS, and angiogenic factors after focal cerebral ischemia: correlations with angiogenesis and cerebral edema |journal=Neurochem. Int. |volume=58 |issue= 8 |pages= 872–9 |year= 2011 |pmid= 21334414 |doi=10.1016/j.neuint.2011.02.014  | pmc=3100427}}
*{{cite journal  |vauthors=Zan L, Zhang X, Xi Y, Wu H, Song Y, Teng G, Li H, Qi J, Wang J |title=Src regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion |journal=Neuroscience |volume=262 |pages= 118–28 |year= 2014 |pmid= 24412374 |doi=10.1016/j.neuroscience.2013.12.060 | pmc=3943922}}
*{{cite journal  |vauthors=Wang J, Fu X, Jiang C, Yu L, Wang M, Han W, Liu L, Wang J |title=Bone marrow mononuclear cell transplantation promotes therapeutic angiogenesis via upregulation of the VEGF-VEGFR2 signaling pathway in a rat model of vascular dementia |journal=Behav. Brain Res. |volume=265 |pages= 171–80 |year= 2014 |pmid= 24589546 |doi=10.1016/j.bbr.2014.02.033 | pmc=4000455}}
*{{cite journal  |vauthors=Ferrara N, Gerber HP |title=The role of vascular endothelial growth factor in angiogenesis |journal=Acta Haematol. |volume=106 |issue= 4 |pages= 148–56 |year= 2002 |pmid= 11815711 |doi=10.1159/000046610  |s2cid=46785882 }}
*{{cite journal  |vauthors=Orpana A, Salven P |title=Angiogenic and lymphangiogenic molecules in hematological malignancies |journal=Leuk. Lymphoma |volume=43 |issue= 2 |pages= 219–24 |year= 2003 |pmid= 11999550 |doi=10.1080/10428190290005964  |s2cid=21908151 }}
*{{cite journal  |vauthors=Afuwape AO, Kiriakidis S, Paleolog EM |title=The role of the angiogenic molecule VEGF in the pathogenesis of rheumatoid arthritis |journal=Histol. Histopathol. |volume=17 |issue= 3 |pages= 961–72 |year= 2003 |pmid= 12168808 }}
*{{cite journal  | author=de Bont ES |title=New vessel formation and aberrant VEGF/VEGFR signaling in acute leukemia: does it matter? |journal=Leuk. Lymphoma |volume=43 |issue= 10 |pages= 1901–9 |year= 2003 |pmid= 12481883 |doi=10.1080/1042819021000015844  |name-list-style=vanc| author2=Neefjes VM  | author3=Rosati S  | display-authors=3  | last4=Vellenga  | first4=E.  | last5=Kamps  | first5=W.A.  |s2cid=45095413 }}
*{{cite journal  | author=Ria R |title=Vascular endothelial growth factor and its receptors in multiple myeloma |journal=Leukemia |volume=17 |issue= 10 |pages= 1961–6 |year= 2003 |pmid= 14513045 |doi= 10.1038/sj.leu.2403076  |name-list-style=vanc| author2=Roccaro AM  | author3=Merchionne F  | display-authors=3  | last4=Vacca  | first4=A  | last5=Dammacco  | first5=F  | last6=Ribatti  | first6=D | doi-access=|s2cid=2335518 }}
*{{cite journal  | author=Caldwell RB |title=Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives |journal=Diabetes Metab. Res. Rev. |volume=19 |issue= 6 |pages= 442–55 |year= 2004 |pmid= 14648803 |doi= 10.1002/dmrr.415  |name-list-style=vanc| author2=Bartoli M  | author3=Behzadian MA  | display-authors=3  | last4=El-Remessy  | first4=Azza E. B.  | last5=Al-Shabrawey  | first5=Mohamed  | last6=Platt  | first6=Daniel H.  | last7=Caldwell  | first7=R. William |s2cid=24931730 }}
*{{cite book |doi=10.1007/978-1-4419-8871-3_1 |chapter=Vasculogenesis and Angiogenesis |title=Angiogenesis in Brain Tumors |series=Cancer Treatment and Research |year=2004 |last1=Patan |first1=Sybill |volume=117 |pages=3–32 |pmid=15015550 |isbn=978-1-4613-4699-9 }}
*{{cite book |doi=10.1007/978-1-4419-8871-3_13 |chapter=Role of VEGF in Developmental Angiogenesis and in Tumor Angiogenesis in the Brain |title=Angiogenesis in Brain Tumors |series=Cancer Treatment and Research |year=2004 |last1=Machein |first1=Marcia Regina |last2=Plate |first2=Karl Heinz |volume=117 |pages=191–218 |pmid=15015562 |isbn=978-1-4613-4699-9 }}
*{{cite journal  |vauthors=Eremina V, Quaggin SE |title=The role of VEGF-A in glomerular development and function |journal=Curr. Opin. Nephrol. Hypertens. |volume=13 |issue= 1 |pages= 9–15 |year= 2004 |pmid= 15090854 |doi=10.1097/00041552-200401000-00002  |s2cid=24212588 }}
*{{cite journal  |vauthors=Storkebaum E, Lambrechts D, Carmeliet P |title=VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection |journal=BioEssays |volume=26 |issue= 9 |pages= 943–54 |year= 2004 |pmid= 15351965 |doi= 10.1002/bies.20092 |s2cid=871954 }}
*{{cite journal  | author=Ribatti D |title=The crucial role of vascular permeability factor/vascular endothelial growth factor in angiogenesis: a historical review |journal=Br. J. Haematol. |volume=128 |issue= 3 |pages= 303–9 |year= 2005 |pmid= 15667531 |doi= 10.1111/j.1365-2141.2004.05291.x |doi-access=  |s2cid=1906340 }}
*{{cite journal  |vauthors=Loureiro RM, D'Amore PA |title=Transcriptional regulation of vascular endothelial growth factor in cancer |journal=Cytokine Growth Factor Rev. |volume=16 |issue= 1 |pages= 77–89 |year= 2005 |pmid= 15733833 |doi= 10.1016/j.cytogfr.2005.01.005 }}
*{{cite journal  |vauthors=Herbst RS, Onn A, Sandler A |title=Angiogenesis and lung cancer: prognostic and therapeutic implications |journal=J. Clin. Oncol. |volume=23 |issue= 14 |pages= 3243–56 |year= 2005 |pmid= 15886312 |doi= 10.1200/JCO.2005.18.853 }}
*{{cite journal  | author=Pufe T |title=The influence of biomechanical parameters on the expression of VEGF and endostatin in the bone and joint system |journal=Ann. Anat. |volume=187 |issue= 5–6 |pages= 461–72 |year= 2006 |pmid= 16320826 |doi=10.1016/j.aanat.2005.06.008  |name-list-style=vanc| author2=Kurz B  | author3=Petersen W  | display-authors=3  | last4=Varoga  | first4=Deike  | last5=Mentlein  | first5=Rolf  | last6=Kulow  | first6=Svea  | last7=Lemke  | first7=Angelika  | last8=Tillmann  | first8=Bernhard  }}
*{{cite journal  |vauthors=Tong JP, Yao YF |title=Contribution of VEGF and PEDF to choroidal angiogenesis: a need for balanced expressions |journal=Clin. Biochem. |volume=39 |issue= 3 |pages= 267–76 |year= 2006 |pmid= 16409998 |doi= 10.1016/j.clinbiochem.2005.11.013 }}
*{{cite journal  |vauthors=Lambrechts D, Carmeliet P |title=VEGF at the neurovascular interface: therapeutic implications for motor neuron disease |journal=Biochim. Biophys. Acta |volume=1762 |issue= 11–12 |pages= 1109–21 |year= 2007 |pmid= 16784838 |doi= 10.1016/j.bbadis.2006.04.005 |doi-access=  }}
*{{cite journal  |vauthors=Matsumoto T, Mugishima H |title=Signal transduction via vascular endothelial growth factor (VEGF) receptors and their roles in atherogenesis |journal=J. Atheroscler. Thromb. |volume=13 |issue= 3 |pages= 130–5 |year= 2006 |pmid= 16835467 |doi=10.5551/jat.13.130  |doi-access=free }}
*{{cite journal  |vauthors=Bogaert E, Van Damme P, Van Den Bosch L, Robberecht W |title=Vascular endothelial growth factor in amyotrophic lateral sclerosis and other neurodegenerative diseases |journal=Muscle Nerve |volume=34 |issue= 4 |pages= 391–405 |year= 2006 |pmid= 16856151 |doi= 10.1002/mus.20609 |s2cid=22086357 }}
*{{cite journal  |vauthors=Mercurio AM, Lipscomb EA, Bachelder RE |title=Non-angiogenic functions of VEGF in breast cancer |journal=Journal of Mammary Gland Biology and Neoplasia |volume=10 |issue= 4 |pages= 283–90 |year= 2006 |pmid= 16924371 |doi= 10.1007/s10911-006-9001-9 |citeseerx=10.1.1.476.2778 |s2cid=16565983 }}
*{{cite journal  |vauthors=Makinde T, Murphy RF, Agrawal DK |title=Immunomodulatory role of vascular endothelial growth factor and angiopoietin-1 in airway remodeling |journal=Curr. Mol. Med. |volume=6 |issue= 8 |pages= 831–41 |year= 2007 |pmid= 17168735 |doi=10.2174/156652406779010795  }}
*{{cite journal  |vauthors=Rini BI, Rathmell WK |title=Biological aspects and binding strategies of vascular endothelial growth factor in renal cell carcinoma |journal=Clin. Cancer Res. |volume=13 |issue= 2 Pt 2 |pages= 741s–746s |year= 2007 |pmid= 17255303 |doi= 10.1158/1078-0432.CCR-06-2110 |doi-access= free }}
* {{cite journal |last1=Jiang |first1=Chao |last2=Zuo |first2=Fangfang |last3=Wang |first3=Yuejuan |last4=Lu |first4=Hong |last5=Yang |first5=Qingwu |last6=Wang |first6=Jian |title=Progesterone Changes VEGF and BDNF Expression and Promotes Neurogenesis After Ischemic Stroke |journal=Molecular Neurobiology |date=1 January 2017 |volume=54 |issue=1 |pages=571–581 |doi=10.1007/s12035-015-9651-y |pmid=26746666 |pmc=4938789 }}
*{{cite journal  |vauthors=Rodgers LS, Lalani S, Hardy KM, Xiang X, Broka D, Antin PB, Camenisch TD |title=Depolymerized hyaluronan induces vascular endothelial growth factor, a negative regulator of developmental epithelial-to-mesenchymal transformation |journal=Circ. Res. |volume=99 |issue= 6 |pages= 583–9 |year= 2006 |pmid= 16931798 |doi= 10.1161/01.RES.0000242561.95978.43 |doi-access= free }}
* {{cite journal | last1 = Qaum | first1 = T | last2 = Xu | first2 = Q | last3 = Joussen | first3 = AM |display-authors=etal | year = 2001 | title = VEGF-initiated blood-retinal barrier breakdown in early diabetes | journal = Invest Ophthalmol Vis Sci | volume = 42 | issue = 10| pages = 2408–2413 | pmid = 11527957 }}
{{refend}}

== External links ==
* {{MeshName|Vascular+Endothelial+Growth+Factors}}
* {{Proteopedia|Vascular_Endothelial_Growth_Factor}} – the Vascular Endothelial Growth Factor Structure in Interactive 3D

{{Angiogenic proteins}}
{{Intercellular signaling peptides and proteins}}
{{Neurotrophins}}
{{Growth factor receptor modulators}}

[[Category:Angiogenesis]]
[[Category:Drugs acting on the cardiovascular system]]
[[Category:Growth factors]]
[[Category:Neurotrophic factors]]
[[Category:Human proteins]]