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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 | doi = 10.1007/s00018-006-6254-9 | volume=63 | 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 | pages=2067–2077}}</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 | url = | journal = J Neuroimmunol | volume = 229 | issue = 1-2| pages = 81–90 | doi=10.1016/j.jneuroim.2010.07.008}}</ref>
==Mechanism Mecanismo ==
[[ImageFicheiro:VEGF receptors.png|thumbminiatura|leftesquerda|200px|TypesTipos ofde VEGF ande theiros seus [[VEGFreceptores receptorsVEGF]].<ref>[http://www.cancerpublications.com/newsletter/colorectal/AIO/v2n3/Article2/a2f1.gif cancerpublications.com.]</ref>]]
AllTodos membersos ofmembros theda familia VEGF familyestimulan stimulateas cellularrespostas responsescelulares byao bindingunirse a receptores de to [[tyrosinetirosina kinasequinase]] receptors (theos [[VEGFRs]]) onda thesuperficie cell surfacecelular, causingcausándolles themque tose dimerize[[dímero|dimericen]] ande becomese activatedactiven throughpor [[transphosphorylationtransfosforilación]], althoughaínda toque differenten sites,difernttes timessitios, andtempos extentse extensión. TheOs receptores VEGF receptorsteñen haveunha anporción extracellularextracelular portionque consistingconsta ofde 7 immunoglobulin-like[[dominio domains,proteico|dominios]] ade tipo inmunoglobulina, singleunha transmembranesoa spanningrexión regiontransmembrana, ande anunha intracellularporción portionintracelular containingque acontén un dominio splitde [[tyrosinetirosina-kinasequinase]] domain. O VEGF-A bindsúnese toa VEGFR-1 ([[Flt-1]]) ande 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> O VEGFR-2 appearsparece tomediar mediatecase almosttodas allas ofrespostas the known cellularcelulares responsescoñecidas todo VEGF. TheA functionfunción ofde VEGFR-1 isestá lesspeor well-defineddefinida, althoughaínda itque isse thoughtcre toque modulate modula a sinalización de 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 }}</ref> AnotherOutra functionfunción ofde VEGFR-1 maypode beser toactuar actcomo asun areceptor dummy/decoy receptorreclamo, sequesteringsecuestrando VEGF fromevitando a súa unión a VEGFR-2 binding (thisisto appearsparece toser beespecialmente particularlyimportante importantdurante duringa vasculogenesisvasculoxénese in theno embryoembrión). O VEGF-C ande o VEGF-D, butpero notnon VEGF-A, areson ligands[[ligando]]s fordun aterceiro third receptorreceeptor ([[FLT4|VEGFR-3/Flt4]]), whichque mediatesmedia a [[lymphangiogenesislinfanxioxénese]]. TheO receptor (VEGFR3) isé theo sitesitio ofde bindingunión ofdos mainprincipais ligandsligandos (VEGFC ande VEGFD), whichos mediatescales perpetualmedian actiona perpetua acción e función de ligandos nas células diana. O VEGF-C pode estimular a linfanxioxénese (vía VEGFR3) e a anxioxénese vía VEGFR2. O VEGF-R3 detectouse en células endoteliais linfáticas no [[corpo lúteo]] de moitas especies, [[vaca]]s, [[búfalo]]s de auga e [[primates]].<ref>{{cite journal | last1 = Ali | first1 = Ibne |display-authors=etal| year = 2013 | title = Expression and functionlocalization of ligandslocally onproduced growth factors regulating lymphangiogenesis during different stages of the estrous cycle in corpus luteum of buffalo" (Bubalus bubalis) | url = http://www.sciencedirect.com/science/article/pii/S0093691X13004263 | journal = Theriogenology | volume = 81| issue = | pages = 428–436| doi=10.1016/j.theriogenology.2013.10.017}}</ref>
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) | url = http://www.sciencedirect.com/science/article/pii/S0093691X13004263 | journal = Theriogenology | volume = 81| issue = | pages = 428–436| doi=10.1016/j.theriogenology.2013.10.017}}</ref>
==Expression==
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