Three vascular endothelial growth-factor receptors (VEGFRs) regulate vascular-endothelial, haematopoietic and lymphatic-endothelial cell function during development and in the adult. Many of these processes require balanced VEGFR signalling, which involves more than one of the VEGFRs.
VEGFR1 signalling seems to be dispensable for endothelial-cell function, but it is essential for the migration of haematopoietic cells. A soluble splice variant of VEGFR1, which lacks the intracellular domain, might function as a VEGF 'trap', and is implicated in preeclampsia during pregnancy. VEGFR1 signal transduction might positively or negatively regulate VEGFR2 activity.
VEGFR2 is absolutely required for endothelial-cell development and survival of blood vessels. Tyrosine phosphorylation sites in VEGFR2 regulate kinase activity and binding of phospholipase C-γ, and the adaptor molecules TSAd, Shb and Sck. VEGFR2-blocking therapies are in use or are being tested for the treatment of human malignancies.
VEGFR3 is required for cardiovascular development and lymphangiogenesis. Certain VEGF family members might induce formation of heterodimers, which involves VEGFR2 and VEGFR3, thereby regulating the phosphorylation of VEGFR3 and consequent signal transduction.
Co-receptors (VEGF-binding molecules that might lack intrinsic catalytic function) such as heparan-sulphate proteoglycans and neuropilins are engaged in the VEGFR signalling complex in a manner that is guided by the VEGF isoform. Co-receptors modulate the duration and quality of VEGFR signalling by the formation of VEGF gradients and by stabilizing the signalling complex. Cell?cell and cell?matrix adhesion molecules that are regulated, for example, by blood flow, affect VEGFR signalling by allowing receptor activation in the absence of VEGF.
The signal from an activated VEGFR is influenced by several factors (the particular VEGF isoform, the possibility of homodimerization or heterodimerization with other VEGFRs, co-receptors or adhesion molecules) in the local milieu.
Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively. Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Takahashi, H. & Shibuya, M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin. Sci. (Lond) 109, 227?241 (2005).
Suto, K., Yamazaki, Y., Morita, T. & Mizuno, H. Crystal structures of novel vascular endothelial growth factors (VEGF) from snake venoms: insight into selective VEGF binding to kinase insert domain-containing receptor but not to fms-like tyrosine kinase-1. J. Biol. Chem. 280, 2126?2131 (2005).
Muller, Y. A. et al. Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc. Natl Acad. Sci. USA 94, 7192?7197 (1997).
De Falco, S., Gigante, B. & Persico, M. G. Structure and function of placental growth factor. Trends Cardiovasc. Med. 12, 241?246 (2002).
Woolard, J. et al. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res. 64, 7822?7835 (2004).
Lee, S., Jilani, S. M., Nikolova, G. V., Carpizo, D. & Iruela-Arispe, M. L. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J. Cell Biol. 169, 681?691 (2005).
Christinger, H. W., Fuh, G., de Vos, A. M. & Wiesmann, C. The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1. J. Biol. Chem. 279, 10382?10388 (2004).
Fuh, G., Li, B., Crowley, C., Cunningham, B. & Wells, J. A. Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor. J. Biol. Chem. 273, 11197?11204 (1998).
Kendall, R. L. & Thomas, K. A. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc. Natl Acad. Sci. USA 90, 10705?10709 (1993).
Ebos, J. M. et al. A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma. Mol. Cancer Res. 2, 315?326 (2004).
Hughes, D. C. Alternative splicing of the human VEGFGR-3/FLT4 gene as a consequence of an integrated human endogenous retrovirus. J. Mol. Evol. 53, 77?99 (2001).
Pugh, C. W. & Ratcliffe, P. J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nature Med. 9, 677?684 (2003).
Gerber, H. P., Condorelli, F., Park, J. & Ferrara, N. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J. Biol. Chem. 272, 23659?23667 (1997).
Nilsson, I. et al. Vascular endothelial growth factor receptor-3 in hypoxia-induced vascular development. FASEB J. 18, 1507?1515 (2004).
Dixelius, J. et al. Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. J. Biol. Chem. 278, 40973?40979 (2003).
Zeng, H., Zhao, D., Yang, S., Datta, K. & Mukhopadhyay, D. Heterotrimeric Gαq/Gα11 proteins function upstream of vascular endothelial growth factor (VEGF) receptor-2 (KDR) phosphorylation in vascular permeability factor/VEGF signaling. J. Biol. Chem. 278, 20738?20745 (2003).
Gallicchio, M. et al. Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor. Blood 105, 1970?1976 (2005).
Guo, D. Q. et al. Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation. J. Biol. Chem. 275, 11216?11221 (2000).
Singh, A. J., Meyer, R. D., Band, H. & Rahimi, N. The carboxyl terminus of VEGFR-2 is required for PKC-mediated down-regulation. Mol. Biol. Cell 16, 2106?2118 (2005).
Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435?439 (1996).
Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439?442 (1996).
Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62?66 (1995). First experimental evidence that VEGFR2 signalling is required for cardiovascular development.
Fong, G. H., Rossant, J., Gertsenstein, M. & Breitman, M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66?70 (1995).
Kearney, J. B. et al. Vascular endothelial growth factor receptor Flt-1 negatively regulates developmental blood vessel formation by modulating endothelial cell division. Blood 99, 2397?2407 (2002).
Levine, R. J. et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672?683 (2004).
Miquerol, L., Langille, B. L. & Nagy, A. Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development 127, 3941?3946 (2000).
Gerber, H. P. et al. VEGF is required for growth and survival in neonatal mice. Development 126, 1149?1159 (1999).
Kamba, T. et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am. J. Physiol. Heart Circ. Physiol. 290, H560?H576 (2005).
Kubo, H. & Alitalo, K. The bloody fate of endothelial stem cells. Genes Dev. 17, 322?329 (2003).
Schatteman, G. C. & Awad, O. Hemangioblasts, angioblasts, and adult endothelial cell progenitors. Anat. Rec. A Discov. Mol. Cell Evol. Biol. 276, 13?21 (2004).
Gerber, H. P. et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417, 954?958 (2002).
Luttun, A. et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nature Med. 8, 831?840 (2002).
Hattori, K. et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment. Nature Med. 8, 841?849 (2002).
Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820?827 (2005). Shows that homing of VEGFR1-positive HPCs to tumour-specific pre-metastatic sites, before the arrival of tumour cells, is required for metastatic spread.
Rafii, S. et al. Contribution of marrow-derived progenitors to vascular and cardiac regeneration. Semin. Cell Dev. Biol. 13, 61?67 (2002).
Wigle, J. T. & Oliver, G. Prox1 function is required for the development of the murine lymphatic system. Cell 98, 769?778 (1999).
Petrova, T. V. et al. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J. 21, 4593?4599 (2002).
Karkkainen, M. J. et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immunol. 5, 74?80 (2004). Shows a requirement for VEGFC signalling during formation of lymphatic-vessel sprouts from embryonic veins. Sprouting in Vegfc−/− whole-mount explants was rescued by VEGFC or VEGFD, but not by VEGFA, which indicates the specificity of VEGFR3 in lymphangiogenesis.
Dumont, D. J. et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282, 946?949 (1998).
Nagy, J. A. et al. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J. Exp. Med. 196, 1497?1506 (2002).
Seetharam, L. et al. A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene 10, 135?147 (1995).
Waltenberger, J., Claesson-Welsh, L., Siegbahn, A., Shibuya, M. & Heldin, C. H. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J. Biol. Chem. 269, 26988?26995 (1994).
Gille, H. et al. A repressor sequence in the juxtamembrane domain of Flt-1 (VEGFR-1) constitutively inhibits vascular endothelial growth factor-dependent phosphatidylinositol 3′-kinase activation and endothelial cell migration. EMBO J. 19, 4064?4073 (2000).
Ito, N., Wernstedt, C., Engstrom, U. & Claesson-Welsh, L. Identification of vascular endothelial growth factor receptor-1 tyrosine phosphorylation sites and binding of SH2 domain-containing molecules. J. Biol. Chem. 273, 23410?23418 (1998).
Matsumoto, T. & Claesson-Welsh, L. VEGF receptor signal transduction. Sci. STKE 2001, RE21 (2001).
Shibuya, M. Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1). Int. J. Biochem. Cell Biol. 33, 409?420 (2001).
Ito, N., Huang, K. & Claesson-Welsh, L. Signal transduction by VEGF receptor-1 wild type and mutant proteins. Cell Signal. 13, 849?854 (2001).
Autiero, M., Luttun, A., Tjwa, M. & Carmeliet, P. Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J. Thromb. Haemost. 1, 1356?1370 (2003).
Hiratsuka, S., Minowa, O., Kuno, J., Noda, T. & Shibuya, M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc. Natl Acad. Sci. USA 95, 9349?9354 (1998). Shows that mice that lack the VEGFR1 tyrosine-kinase domain are healthy, in contrast to Vegfr1 -null mice, which die at E8.5?9, owing to an overgrowth of endothelial cells (reference 23). Together, these data strongly indicate that the kinase activity of VEGFR1 is not required for endothelial-cell development.
Hiratsuka, S. et al. Membrane fixation of vascular endothelial growth factor receptor 1 ligand-binding domain is important for vasculogenesis and angiogenesis in mice. Mol. Cell Biol. 25, 346?354 (2005). Shows that anchoring of the VEGFR1 extracellular domain to the plasma membrane is important, as 50% of the mice that lack both the tyrosine-kinase and the transmembrane domains die at E8.5?9 because of vascular defects.
Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194?1201 (2001).
Zeng, H., Dvorak, H. F. & Mukhopadhyay, D. Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) receptor-1 down-modulates VPF/VEGF receptor-2-mediated endothelial cell proliferation, but not migration, through phosphatidylinositol 3-kinase-dependent pathways. J. Biol. Chem. 276, 26969?26979 (2001).
Rahimi, N., Dayanir, V. & Lashkari, K. Receptor chimeras indicate that the vascular endothelial growth factor receptor-1 (VEGFR-1) modulates mitogenic activity of VEGFR-2 in endothelial cells. J. Biol. Chem. 275, 16986?16992 (2000).
Roberts, D. M. et al. The vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR-1) modulates Flk-1 (VEGFR-2) signaling during blood vessel formation. Am. J. Pathol. 164, 1531?1535 (2004).
Carmeliet, P. et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nature Med. 7, 575?583 (2001).
Autiero, M. et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nature Med. 9, 936?943 (2003).
Dougher, M. & Terman, B. I. Autophosphorylation of KDR in the kinase domain is required for maximal VEGF-stimulated kinase activity and receptor internalization. Oncogene 18, 1619?1627 (1999).
Takahashi, T., Yamaguchi, S., Chida, K. & Shibuya, M. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-γ and DNA synthesis in vascular endothelial cells. EMBO J. 20, 2768?2678 (2001).
Sakurai, Y., Ohgimoto, K., Kataoka, Y., Yoshida, N. & Shibuya, M. Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc. Natl Acad. Sci. USA 102, 1076?1081 (2005). Mice that express a mutated Tyr1173Phe VEGFR2 (which no longer binds to PLCγ) die at E8.5?9 because of vascular defects that are similar to those that are observed in Vegfr2 -null mutant mice (reference 22). These data show that a single VEGFR2 tyrosine residue is required for vascular development.
Holmqvist, K. et al. The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration. J. Biol. Chem. 279, 22267?22275 (2004).
Dayanir, V., Meyer, R. D., Lashkari, K. & Rahimi, N. Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol 3-kinase and cell proliferation. J. Biol. Chem. 276, 17686?17692 (2001).
Fujio, Y. & Walsh, K. Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J. Biol. Chem. 274, 16349?16354 (1999).
Warner, A. J., Lopez-Dee, J., Knight, E. L., Feramisco, J. R. & Prigent, S. A. The Shc-related adaptor protein, Sck, forms a complex with the vascular-endothelial-growth-factor receptor KDR in transfected cells. Biochem. J. 347, 501?509 (2000).
Sakai, R. et al. The mammalian ShcB and ShcC phosphotyrosine docking proteins function in the maturation of sensory and sympathetic neurons. Neuron 28, 819?833 (2000).
Shu, X., Wu, W., Mosteller, R. D. & Broek, D. Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol. Cell Biol. 22, 7758?7768 (2002).
Meadows, K. N., Bryant, P. & Pumiglia, K. Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation. J. Biol. Chem. 276, 49289?49298 (2001).
Takahashi, T., Ueno, H. & Shibuya, M. VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 18, 2221?2230 (1999).
Kroll, J. & Waltenberger, J. The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J. Biol. Chem. 272, 32521?32527 (1997).
Matsumoto, T. et al. VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. EMBO J. 24, 2342?2353 (2005). Mice that lack the signalling molecule TSAd have reduced tumour growth and vascularization. Moreover, the authors show VEGF-induced complex formation between TSAd and Src, which possibly regulates Src activation and permeability.
Zeng, H., Sanyal, S. & Mukhopadhyay, D. Tyrosine residues 951 and 1059 of vascular endothelial growth factor receptor-2 (KDR) are essential for vascular permeability factor/vascular endothelial growth factor-induced endothelium migration and proliferation, respectively. J. Biol. Chem. 276, 32714?32719 (2001).
Lamalice, L., Houle, F., Jourdan, G. & Huot, J. Phosphorylation of tyrosine 1214 on VEGFR2 is required for VEGF-induced activation of Cdc42 upstream of SAPK2/p38. Oncogene 23, 434?445 (2004).
Issbrucker, K. et al. p38 MAP kinase ? a molecular switch between VEGF-induced angiogenesis and vascular hyperpermeability. FASEB J. 17, 262?264 (2003).
Matsumoto, T., Turesson, I., Book, M., Gerwins, P. & Claesson-Welsh, L. p38 MAP kinase negatively regulates endothelial cell survival, proliferation, and differentiation in FGF-2-stimulated angiogenesis. J. Cell Biol. 156, 149?160 (2002).
McMullen, M. E., Bryant, P. W., Glembotski, C. C., Vincent, P. A. & Pumiglia, K. M. Activation of p38 has opposing effects on the proliferation and migration of endothelial cells. J. Biol. Chem. 280, 20995?21003 (2005).
Rousseau, S., Houle, F., Landry, J. & Huot, J. p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 15, 2169?2177 (1997).
Abedi, H. & Zachary, I. Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J. Biol. Chem. 272, 15442?15451 (1997).
Le Boeuf, F., Houle, F. & Huot, J. Regulation of vascular endothelial growth factor receptor 2-mediated phosphorylation of focal adhesion kinase by heat shock protein 90 and Src kinase activities. J. Biol. Chem. 279, 39175?39185 (2004).
Hart, M. J., Callow, M. G., Souza, B. & Polakis, P. IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs. EMBO J. 15, 2997?3005 (1996).
Yamaoka-Tojo, M. et al. IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species?dependent endothelial migration and proliferation. Circ. Res. 95, 276?283 (2004).
Karkkainen, M. J. et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nature Genet. 25, 153?159 (2000). Establishes that mutations that inactivate the tyrosine-kinase function of VEGFR3 cause lymphoedema in humans.
Fournier, E., Dubreuil, P., Birnbaum, D. & Borg, J. P. Mutation at tyrosine residue 1337 abrogates ligand-dependent transforming capacity of the FLT4 receptor. Oncogene 11, 921?931 (1995).
Saharinen, P., Tammela, T., Karkkainen, M. J. & Alitalo, K. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol. 25, 387?395 (2004).
Makinen, T. et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 20, 4762?4773 (2001).
Wang, J. F., Zhang, X. & Groopman, J. E. Activation of vascular endothelial growth factor receptor-3 and its downstream signaling promote cell survival under oxidative stress. J. Biol. Chem. 279, 27088?27097 (2004).
Korpelainen, E. I., Karkkainen, M., Gunji, Y., Vikkula, M. & Alitalo, K. Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene 18, 1?8 (1999).
Yuan, L. et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129, 4797?4806 (2002).
Ashikari-Hada, S., Habuchi, H., Kariya, Y. & Kimata, K. Heparin regulates vascular endothelial growth factor165-dependent mitogenic activity, tube formation, and its receptor phosphorylation of human endothelial cells. Comparison of the effects of heparin and modified heparins. J. Biol. Chem. 280, 31508?31515 (2005).
Stalmans, I. et al. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J. Clin. Invest. 109, 327?336 (2002).
Ruhrberg, C. et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 16, 2684?2698 (2002). Shows that the tissue distribution of VEGFA and subsequent vascular patterning is modulated by interactions with heparan-sulphate proteoglycans.
Ibrahimi, O. A., Zhang, F., Hrstka, S. C., Mohammadi, M. & Linhardt, R. J. Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly. Biochemistry 43, 4724?4730 (2004).
Jakobsson, L. et al. Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis. Dev. Cell (in the press).
Soker, S., Takashima, S., Miao, H. Q., Neufeld, G. & Klagsbrun, M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735?745 (1998).
West, D. C. et al. Interactions of multiple heparin binding growth factors with neuropilin-1 and potentiation of the activity of fibroblast growth factor-2. J. Biol. Chem. 280, 13457?13464 (2005).
Miao, H. Q., Lee, P., Lin, H., Soker, S. & Klagsbrun, M. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J. 14, 2532?2539 (2000).
Tzima, E. et al. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437, 426?431 (2005).
Bazzoni, G. & Dejana, E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol. Rev. 84, 869?901 (2004).
Serini, G., Valdembri, D. & Bussolino, F. Integrins and angiogenesis: a sticky business. Exp. Cell Res. 312, 651?658 (2006).
Soldi, R. et al. Role of αvβ3 integrin in the activation of vascular endothelial growth factor receptor-2. EMBO J. 18, 882?892 (1999).
Reynolds, A. R. et al. Elevated Flk1 (vascular endothelial growth factor receptor 2) signaling mediates enhanced angiogenesis in β3-integrin-deficient mice. Cancer Res. 64, 8643?8650 (2004).
Ventura, A. & Pelicci, P. G. Semaphorins: green light for redox signaling? Sci. STKE 2002, PE44 (2002).
Cheng, L. et al. Anti-chemorepulsive effects of vascular endothelial growth factor and placental growth factor-2 in dorsal root ganglion neurons are mediated via neuropilin-1 and cyclooxygenase-derived prostanoid production. J. Biol. Chem. 279, 30654?30661 (2004).
Ny, A., Autiero, M. & Carmeliet, P. Zebrafish and Xenopus tadpoles: small animal models to study angiogenesis and lymphangiogenesis. Exp. Cell Res. 312, 684?693 (2006).
Jekely, G., Sung, H. H., Luque, C. M. & Rorth, P. Regulators of endocytosis maintain localized receptor tyrosine kinase signaling in guided migration. Dev. Cell 9, 197?207 (2005). Shows that endocytosis of the activated D. melanogaster PVR (PDGF/VEGF) receptor ensures a localized intracellular response to guidance cues.
Bruckner, K. et al. The PDGF/VEGF receptor controls blood cell survival in Drosophila. Dev. Cell 7, 73?84 (2004).
Habeck, H., Odenthal, J., Walderich, B., Maischein, H. & Schulte-Merker, S. Analysis of a zebrafish VEGF receptor mutant reveals specific disruption of angiogenesis. Curr. Biol. 12, 1405?1412 (2002).
Lawson, N. D., Vogel, A. M. & Weinstein, B. M. Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev. Cell 3, 127?136 (2002).
Lawson, N. D., Mugford, J. W., Diamond, B. A. & Weinstein, B. M. phospholipase Cγ-1 is required downstream of vascular endothelial growth factor during arterial development. Genes Dev. 17, 1346?1351 (2003).
Lee, P. et al. Neuropilin-1 is required for vascular development and is a mediator of VEGF-dependent angiogenesis in zebrafish. Proc. Natl Acad. Sci. USA 99, 10470?10475 (2002).
Sumanas, S. & Lin, S. Ets1-related protein is a key regulator of vasculogenesis in zebrafish. PLoS Biol. 4, e10 (2006).
Senger, D. R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983?985 (1983).
Bates, D. O. & Harper, S. J. Regulation of vascular permeability by vascular endothelial growth factors. Vascul. Pharmacol. 39, 225?237 (2003).
Roberts, W. G. & Palade, G. E. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J. Cell Sci. 108, 2369?2379 (1995).
Baluk, P. et al. Endothelial gaps: time course of formation and closure in inflamed venules of rats. Am. J. Physiol. 272, L155?L170 (1997).
Dvorak, H. F., Nagy, J. A., Feng, D., Brown, L. F. & Dvorak, A. M. Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr. Opin. Microbiol. Immunol. 237, 97?132 (1999).
Weis, S. M. & Cheresh, D. A. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437, 497?504 (2005).
Fulton, D. et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597?601 (1999).
Fukumura, D. et al. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc. Natl Acad. Sci. USA 98, 2604?2609 (2001).
Eliceiri, B. P. et al. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol. Cell 4, 915?924 (1999). Using mice that lack individual Src family members ( Src-, Fyn - and Yes -null mutants), this report shows that VEGF-induced permeability is dependent on Src or Yes but not Fyn.
Kiba, A., Sagara, H., Hara, T. & Shibuya, M. VEGFR-2-specific ligand VEGF-E induces non-edematous hyper-vascularization in mice. Biochem. Biophys. Res. Commun. 301, 371?377 (2003).
Jain, R. K., Duda, D. G., Clark, J. W. & Loeffler, J. S. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nature Clin. Pract. Oncol. 3, 24?40 (2006).
Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58?62 (2005).
Doggrell, S. A. Pegaptanib: the first antiangiogenic agent approved for neovascular macular degeneration. Expert. Opin. Pharmacother. 6, 1421?1423 (2005).
Carmeliet, P. et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nature Med. 5, 495?502 (1999).
Zelzer, E. et al. Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 129, 1893?1904 (2002).
Maes, C. et al. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech. Dev. 111, 61?73 (2002).
Maes, C. et al. Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival. J. Clin. Invest. 113, 188?199 (2004).
Aase, K. et al. Vascular endothelial growth factor-B-deficient mice display an atrial conduction defect. Circulation 104, 358?364 (2001).
Bellomo, D. et al. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ. Res. 86, E29?E35 (2000).
Jeltsch, M. et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276, 1423?1425 (1997).
Baldwin, M. E. et al. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol. Cell Biol. 25, 2441?2449 (2005).
Fong, G. H., Zhang, L., Bryce, D. M. & Peng, J. Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development 126, 3015?3025 (1999).
Hiratsuka, S. et al. Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res. 61, 1207?1213 (2001).
Hiratsuka, S. et al. Vascular endothelial growth factor A (VEGF-A) is involved in guidance of VEGF receptor-positive cells to the anterior portion of early embryos. Mol. Cell Biol. 25, 355?363 (2005).
Makinen, T. et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nature Med. 7, 199?205 (2001).
Kawasaki, T. et al. A requirement for neuropilin-1 in embryonic vessel formation. Development 126, 4895?4902 (1999).
Kitsukawa, T. et al. Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron 19, 995?1005 (1997).
Kitsukawa, T., Shimono, A., Kawakami, A., Kondoh, H. & Fujisawa, H. Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development 121, 4309?4318 (1995).
Giger, R. J. et al. Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins. Neuron 25, 29?41 (2000).
Takashima, S. et al. Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc. Natl Acad. Sci. USA 99, 3657?3662 (2002).
We thank colleagues and lab members for sharing their insights and for stimulating discussions. Owing to space limitations, we have not been able to cite all relevant work; we apologize to those whose work has been omitted. The authors are supported by the Swedish Research Council, the Swedish Cancer Foundation, the EU 6th framework program Lymphangiogenomics and Angiotargeting, the Association for International Cancer Research (to A.D.) and the Wenner?Gren Foundations (to J.K.).
The authors declare no competing financial interests.
Establishment of the embryonic vascular system.
Formation of new blood vessels from already established vasculature.
- Receptor tyrosine kinase
Single transmembrane growth-factor receptor with an intracellular enzymatic (tyrosine kinase) domain that is activated by growth-factor binding, resulting in the transfer of phosphate groups onto tyrosine residues.
- Heparan sulphate proteoglycans
(HSPGs). Transmembrane, lipid-anchored or secreted proteins that interact, through covalently linked heparan sulphate chains, with many proteins, including VEGF.
Transmembrane glycoproteins that have been characterized as receptors for semaphorins in neuronal guidance and as co-receptors for VEGFs in angiogenesis.
Abnormal and excessive accumulation of fluid in the tissue, which might be localized or generalised.
A pregnancy disorder that is characterized by hypertension and proteinuria occurring after the 20th week of gestation.
Accumulation of serous fluid in the peritoneal cavity.
Specialized micro-invaginations of the plasma membrane.
- Vesiculovacuolar organelle
(VVO). Transendothelial channel created by fusion of vesicles, for example, in response to VEGF.
- Cardinal vein
An important drainage vessel for deoxygenated blood in the embryo.
- Mesenchymal cell
Embryonic connective (supporting)-tissue cell.
Formation of new blood vessels, often in conjunction with disease processes.
- Age-related macular degeneration
(AMD). Degeneration of the cells of the macula (part of the retina) in the eye and neovascularization in the choroids, which results in blurred vision and can cause blindness. Leading cause of blindness among the elderly in the western world.
- Fenestrated capillaries
Small, permeable blood vessels with circular pores, covered with a thin diaphragm.
- Tip cell
The endothelial cell that heads a blood-vessel sprout during angiogenesis.
Cells that surround small blood vessels, particularly numerous around post-capillary venules.
Transmembrane or secreted molecules that guide the path of growing nerve axons.
About this article
Cite this article
Olsson, AK., Dimberg, A., Kreuger, J. et al. VEGF receptor signalling ? in control of vascular function. Nat Rev Mol Cell Biol 7, 359–371 (2006). https://doi.org/10.1038/nrm1911
Brain expression of the vascular endothelial growth factor gene family in cognitive aging and alzheimer’s disease
Molecular Psychiatry (2021)
Resequencing and SNP discovery of Amur ide (Leuciscus waleckii) provides insights into local adaptations to extreme environments
Scientific Reports (2021)
Anti-cancer activity of two novel heterocyclic compounds through modulation of VEGFR and miR-122 in mice bearing Ehrlich ascites carcinoma
European Journal of Pharmacology (2021)
New insights into the role of co-receptor neuropilins in tumour angiogenesis and lymphangiogenesis and targeted therapy strategies
Journal of Drug Targeting (2021)