Abstract
Vascular endothelial growth factor receptor-1 (VEGFR-1) is a member of the VEGFR family, and binds VEGF-A, PlGF, and VEGF-B. An important feature of VEGFR-1 is that, unlike other VEGFR genes, it expresses two types of mRNA, one for a full-length receptor and another for a soluble short protein known as soluble VEGFR-1 (sFlt-1). The binding-affinity of VEGFR-1 for VEGF-A is one order of magnitude higher than that of VEGFR-2, whereas the kinase activity of VEGFR-1 is about 10-fold weaker than that of VEGFR-2. Through its ligand-binding region and by trapping ligands, VEGFR-1 plays a negative role in angiogenesis at embryogenesis. In adulthood, however, VEGFR-1 is expressed not only on endothelial cells but also on macrophages, and promotes the function of macrophages, inflammatory diseases, cancer metastasis, and atherosclerosis via its kinase activity. Soluble VEGFR-1 is abnormally overexpressed in the placenta of preeclamptic patients, and suggested to cause the major pathological symptoms on the maternal side such as hypertension and renal dysfunction, most likely by blocking the physiological VEGF-A. VEGFR-1 including its soluble form is involved in a variety of human illnesses, making it an important target in the development of new strategies to suppress disease.
Similar content being viewed by others
References
Risau W (1997) Mechanism of angiogenesis. Nature 38(6):671–674
Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev Aug 25(4):581–611
Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312:549–560
Alitalo K, Carmeliet P (2002) Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1:219–227
De Vries C, Escobedo nJ A, Ueno H et al (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991
Terman BI, Dougher-Vermazen M, Carrion ME et al (1992) Identification of the KDR tyrosine kinase as a receptor for Vascular Endothelial Growth Factor. Biochem Biophys Res Commun 187:1579–1586
Shibuya M, Yamaguchi S, Yamane A et al (1990) Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene 5:519–524
Keyt BA, Nguyen HV, Berleau LT et al (1996) Identification of vascular endothelial growth factor determinanats for binding KDR and FLT-1 receptors. J Biol Chem 271:5638–5646
Tanaka K, Yamaguchi S, Sawano A et al (1997) Characterization of the extracellular domain in the Vascular Endothelial Growth Factor Receptor-1 (Flt-1 tyrosine kinase). Jpn J Cancer Res 88:867–876
Sawano A, Takahashi T, Yamaguchi S et al (1996) Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for Placenta Growth Factor (PlGF), which is related to Vascular Endothelial Growth Factor (VEGF). Cell Growth Differ 7:213–221
Waltenberger J, Claesson-Welsh L, Siegbahn A et al (1994) Different signal transduction properties of KDR and Flt1, two receptors for Vascular Endothelial Growth Factor. J Biol Chem 269:26988–26995
Seetharam L, Gotoh N, Maru Y et al (1995) A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene 10:135–147
Cunningham SA, Waxham MN, Arrate PM et al (1995) Interaction of the Flt-1 tyrosine kinase receptor with the p85 subunit of phosphatidylinositol 3-kinase. J Biol Chem 270:20254–20257
Sawano A, Takahashi T, Yamaguchi S et al (1997) The phosphorylated 1169-tyrosine containing region of Flt-1 kinase (VEGFR-1) is a major binding site for PLCγ. Biochem Biophys Res Commun 238:487–491
Ito N, Huang K, Claesson-Welsh L (2001) Signal transduction by VEGF receptor-1 wild type and mutant proteins. Cell Signal 13:849–854
Takahashi T, Yamaguchi S, Chida K et al (2001) 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 20:2768–2778
Sakurai Y, Ohgimoto K, Kataoka Y et al (2005) Essential role of Flk-1 (vascular endothelial growth factor receptor-2) tyrosine residue-1173 in vasculogenesis in mice. Proc Natl Acad Sci USA 102:1076–1081
Fong G-H, Rossant J, Gertsentein M et al (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70
Hiratsuka S, Minowa O, Kuno J et al (1998) Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA 95:9349–9354
Hiratsuka S, Nakao K, Nakamura K et al (2005) Membrane-fixation of VEGFR1 ligand-binding domain is important for vasculogenesis/angiogenesis in mice. Mol Cell Biol 25:346–354
Luttun A, Tjwa M, Moons L et al (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8(8):831–840
De Bandt M, Ben Mahdi MH, Ollivier V et al (2003) Blockade of vascular endothelial growth factor receptor I (VEGF-RI), but not VEGF-RII, suppresses joint destruction in the K/BxN model of rheumatoid arthritis. J Immunol 171:4853–4859
Lyden D, Hattori K, Dias S et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201
Murakami M, Iwai S, Hiratsuka S et al (2006) Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocyte/macrophages. Blood 108:1849–1856
Barleon B, Sozzani S, Zhou D et al (1996) Migration of human monocytes in response to Vascular Endothelilal Growth Factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87:3336–3343
Clauss M, Weicht H, Breier G et al (1996) The Vascular Endothelial Growth Factor Receptor Flt-1 madiates biological activities. J Biol Chem 271:17629–17634
Sawano A, Iwai S, Sakurai Y et al (2001) Vascular Endothelial Growth Factor Receptor-1 (Flt-1) is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 97:785–791
Kiba A, Sagara H, Hara T et al (2003) VEGFR-2-specific ligand VEGF-E induces non-edematous hyper-vascularization in mice. Biochem Biophys Res Commun 301:371–377
Hiratsuka S, Maru Y, Okada A et al (2001) Involvement of Flt-1 tyrosine kinase (Vascular Endothelial Growth Factor Receptor-1) in pathological angiogenesis. Cancer Res 61:1207–1213
Hiratsuka S, Nakamura K, Iwai S et al (2002) MMP9 induction by Vascular Endothelial Growth Factor Receptor-1 is involved in lung specific metastasis. Cancer Cell 2:289–300
Kaplan RN, Riba RD, Zacharoulis S et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827
Ohtani K, Egashira K, Hiasa KI et al (2004) Blockade of vascular endothelial growth factor suppresses experimental restenosis after intraluminal injury by inhibiting recruitment of monocyte lineage cells. Circulation 110:2444–2452
Zhao Q, Egashira K, Hiasa KI et al (2004) Essential role of vascular endothelial growth factor and flt-1 signals in neointimal formation after periadventitial injury. Arterioscler Thromb Vasc Biol 24:2284–2289
Niida S, Kondo T, Hiratsuka S et al (2005) Vascular endothelial growth factor receptor-1 signaling is essential for osteoclast development and bone-marrow formation in CSF-1-deficient mice. Proc Natl Acad Sci USA 102:14016–14021
Takahashi H, Hattori S, Iwamatsu A et al (2004) A novel snake venom vascular endothelial growth factor (VEGF) predominantly induces vascular permeability through preferential signaling via VEGF receptor-1. J Biol Chem 279:46304–46314
Kendall RL, Thomas KA (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90:10705–10709
Helske S, Vuorela P, Carpen O et al (2001) Expression of vascular endothelial growth factor receptors 1, 2 and 3 in placentas from normal and complicated pregnancies. Mol Hum Reprod 7:205–210
Koga K, Osuga Y, Yoshino O et al (2003) Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab 88:2348–2351
Maynard SE, Min JY, Merchan J et al (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658
Levine RJ, Maynard SE, Qian C et al (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683
Dikov MM, Ohm JE, Ray N et al (2005) Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol 174:215–222
Yamagishi S, Yonekura H, Yamamoto Y et al (1999) Vascular endothelial growth factor acts as a pericyte mitogen under hypoxic conditions. Lab Invest Apr 79(4):501–509
Acknowledgements
This work was supported by Grants-in-aid for Special Project Research on Cancer-Bioscience (12215024, 17014020) from the Ministry of Education, Science, Sports and Culture of Japan and for the program ‘Research for the Future’ of the Japan Society for the Promotion of Science, and the program ‘Promotion of Fundamental Research in Health Sciences’ from the Organization for Pharmaceutical Safety and Research (OPSR).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shibuya, M. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. Angiogenesis 9, 225–230 (2006). https://doi.org/10.1007/s10456-006-9055-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10456-006-9055-8