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01-12-2006 | Review

Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis

Author: Masaubmi Shibuya

Published in: Angiogenesis | Issue 4/2006

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.

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):581–611CrossRef

Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312:549–560CrossRefPubMed

Alitalo K, Carmeliet P (2002) Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1:219–227CrossRefPubMed

De Vries C, Escobedo nJ A, Ueno H et al (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991CrossRefPubMed

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 187:1579–1586CrossRefPubMed

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 5:519–524PubMed

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 271:5638–5646CrossRefPubMed

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 88:867–876PubMed

10.

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 7:213–221PubMed

11.

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 269:26988–26995PubMed

12.

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 10:135–147PubMed

13.

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 270:20254–20257CrossRefPubMed

14.

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 238:487–491CrossRefPubMed

15.

Ito N, Huang K, Claesson-Welsh L (2001) Signal transduction by VEGF receptor-1 wild type and mutant proteins. Cell Signal 13:849–854CrossRefPubMed

16.

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 20:2768–2778CrossRefPubMed

17.

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 102:1076–1081CrossRefPubMed

18.

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 376:66–70CrossRefPubMed

19.

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 95:9349–9354CrossRefPubMed

20.

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 25:346–354CrossRefPubMed

21.

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):831–840PubMed

22.

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 171:4853–4859PubMed

23.

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 7:1194–1201CrossRefPubMed

24.

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 108:1849–1856CrossRefPubMed

25.

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 87:3336–3343PubMed

26.

Clauss M, Weicht H, Breier G et al (1996) The Vascular Endothelial Growth Factor Receptor Flt-1 madiates biological activities. J Biol Chem 271:17629–17634CrossRefPubMed

27.

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 97:785–791CrossRefPubMed

28.

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 301:371–377CrossRefPubMed

29.

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 61:1207–1213PubMed

30.

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 2:289–300CrossRefPubMed

31.

Kaplan RN, Riba RD, Zacharoulis S et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827CrossRefPubMed

32.

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 110:2444–2452CrossRefPubMed

33.

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 24:2284–2289CrossRefPubMed

34.

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 102:14016–14021CrossRefPubMed

35.

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 279:46304–46314CrossRefPubMed

36.

Kendall RL, Thomas KA (1993) Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90:10705–10709CrossRefPubMed

37.

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 7:205–210CrossRefPubMed

38.

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 88:2348–2351CrossRefPubMed

39.

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 111:649–658CrossRefPubMed

40.

Levine RJ, Maynard SE, Qian C et al (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683CrossRefPubMed

41.

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 174:215–222PubMed

42.

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

Title: Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis
Author: Masaubmi Shibuya
Publication date: 01-12-2006
Publisher: Kluwer Academic Publishers
Published in: Angiogenesis / Issue 4/2006
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-006-9055-8

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