Development - VEGF-family signaling

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VEGF-family signaling

The vascular endothelial growth factor (VEGF) family of ligands and receptors is crucial for vascular development and neovascularization in physiological and pathological processes in both embryos, and in adults [1].

VEGFs belong to a family of homodimeric glycoproteins that contains five members (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and Placenta growth factor PLGF). VEGFs bind to three different VEGF-receptor tyrosine kinases (VEGFR-1, VEGFR-2 and VEGFR-3). Upon ligation, VEGF-receptors dimerize, autophosphorylate and, thereby transduce signals that direct cellular function [2].

VEGFR-1 is a high-affinity receptor for VEGF-A, VEGF-B and PLGF [3], [4], [5]. It is expressed in vascular endothelial and some non-endothelial cells including haematopoietic stem cells, macrophages and monocytes [1], [6].

VEGFR-2 is highly specific towards VEGF-A [1]. However, it also binds the processed forms of VEGF-C and VEGF-D [7]. VEGFR-2 is expressed in both vacular endothelial and lymphatic endothelial cells. Its expression has also been demonstrated in several other cell types such as megakaryocytes and haematopoietic stem cells.

VEGFR-3 is highly specific towards VEGF-C and VEGF-D [8], [9]. It is expressed at high levels in lymphatic endothelial cells, but also is important for vascular development [10].

VEGF-receptor function is enhanced by interaction with co-receptors of VEGFs Neuropilin-1 and Neuropilin-2 [11], [12], [13]. VEGF-A, VEGF-B and PLGF bind to Neuropilin-1, whereas VEGF-A, VEGF-C and PLGF bind to Neuropilin-2 [14], [15]. Neuropilin-1 stabilizes the VEGFR-2 complex with VEGF-A [13], [16], whereas Neuropilin-2 might be required for stabilizing the complex of VEGFR-3 with its ligands [17].

L1 cell adhesion molecule (L1CAM) and VEGF-A bind to alpha-V/beta-3 integrin and to VEGFR-2 to induce endothelial cell adhesion, migration, and survival [18], [19].

Extracellular matrix protein Fibronectin binds to alpha-5/beta-1 integrin and VEGFR-3 and induces association of the alpha-5/beta-1 integrin with VEGFR-3. Both Fibronectin and VEGF-A bind to VEGFR-3 and selectively promote the growth of lymphatic endothelial cells [20].

VEGFR-1 binds to Src homology 2 domain containing transforming protein (Shc) and Growth factor receptor bound 2 (GRB2). VEGFR-1 also phosphorylates Phospholipase C gamma (PLC-gamma) [21], [22], [23]. VEGFR-1 also can interact with the regulatory subunit of Phosphatidylinositol 3-kinase (PI3K reg class 1A) [24].

VEGFR-2 is considered to be a major mediator of several physiological and pathological effects of VEGF-A on endothelial cells. The activated VEGFR-2 phosphorylates and activates PLC-gamma, which in turn results in hydrolysis of the membrane Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and generation of the second messengers 1,2-Diacylglycerol (DAG) and Inositol (1,4,5)-trisphosphate (IP3). DAG is a physiological activator of conventional isoforms of Protein kinase C, such as PKC-alpha, whereas binds to a specific present on the endoplasmic reticulum (IP3 receptor), resulting in the release of intracellular stored Ca(2+) [2].

Activation of ERKs by VRGFR-2 proceeds via a major pathway that involves association with the adapter proteins Shc and GRB2, subsequent stimulation of the guanine nucleotide exchange factor, Son of sevenless proteins (SOS) and activation of the v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras). H-Ras in turn activates v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2)/ Mitogen-activated protein kinases 1 and 3 (ERK1/2) cascade, resulting in cell proliferation [1].

VEGFR-2 also binds and activates PI3K reg class 1A [25] followed by the activation of the catalytic subunits of PI3K (PI3K cat class 1A). This results in increase in the lipid Phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) and in activation of the v-AKT murine thymoma viral oncogene homolog (AKT). AKT-signaling pathway regulates cellular survival by inhibiting pro-apoptotic pathways [2].

The activated VEGFR-3 phosphorylates adapter proteins Shc and GRB2, and Shc/GRB2 protein complex can mediate the signal for lymphatic endothelial cell growth [26], [27]. The activation of the classical ERK1/2 pathway by VEGFR-3 is considered to be independent of H-Ras. Incidentally, PLC-gamma/ PKC-alpha-dependent activation of the ERK1/2 cascade has indeed been reported [28]. VEGFR-3 activation also leads to induction of PI3K and stimulation of AKT. AKT signaling is important for lymphatic and blood endothelial cell survival [29].

It is suggested that VEGFR-1 has a dual function in angiogenesis where it plays negative and positive roles depending on the circumstances.

VEGFR-1 possesses weak kinase activity that is about 10 times lower than that of VEGFR-2 [6]. However, VEGFR-1 is capable of transducing signals in endothelial cells [6], [30] as well as monocytes and macrophages [2], [31], [32], [33].

VEGFR-1 (or its soluble form sVEGFR-1) [2], [34] is possibly a "decoy" receptor that sequesters VEGF-A and thus renders it less available to the functional VEGFR-2 [13]. VEGFR-1 also can directly bind to Neuropilin-1, thus competing with VEGF-A. Such inactivated Neuropilin-1 is unable to interact with VEGFR-2 [11].

On the other hand, binding of PLGF to VEGFR-1 in endothelial cells leads to displacement of VEGF-A from VEGFR-1. As a result, increased amounts of VEGF-A are available to bind to the mitogenic response-inducing receptor VEGFR-2 [35]. Moreover, activation of VEGFR-1 by PLGF results in intermolecular transphosphorylation of VEGFR-2, and thereby amplification of the angiogenesis through VEGFR-2 [36].

The signal-transduction capacity of VEGFR-3 is directly enhanced by heterodimeric-complex formation with VEGFR-2 in primary human endothelial cells expressing both receptors [37].

References:

  1. Zachary I, Gliki G
    Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovascular research 2001 Feb 16;49(3):568-81
  2. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L
    VEGF-receptor signal transduction. Trends in biochemical sciences 2003 Sep;28(9):488-94
  3. de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT
    The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science (New York, N.Y.) 1992 Feb 21;255(5047):989-91
  4. Park JE, Chen HH, Winer J, Houck KA, Ferrara N
    Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. The Journal of biological chemistry 1994 Oct 14;269(41):25646-54
  5. Olofsson B, Korpelainen E, Pepper MS, Mandriota SJ, Aase K, Kumar V, Gunji Y, Jeltsch MM, Shibuya M, Alitalo K, Eriksson U
    Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 1998 Sep 29;95(20):11709-14
  6. Shibuya M
    Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1). The international journal of biochemistry & cell biology 2001 Apr;33(4):409-20
  7. Clauss M
    Molecular biology of the VEGF and the VEGF receptor family. Seminars in thrombosis and hemostasis 2000;26(5):561-9
  8. Pajusola K, Aprelikova O, Korhonen J, Kaipainen A, Pertovaara L, Alitalo R, Alitalo K
    FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer research 1992 Oct 15;52(20):5738-43
  9. Karkkainen MJ, Makinen T, Alitalo K
    Lymphatic endothelium: a new frontier of metastasis research. Nature cell biology 2002 Jan;4(1):E2-5
  10. Saharinen P, Tammela T, Karkkainen MJ, Alitalo K
    Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends in immunology 2004 Jul;25(7):387-95
  11. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M
    Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998 Mar 20;92(6):735-45
  12. Rossignol M, Gagnon ML, Klagsbrun M
    Genomic organization of human neuropilin-1 and neuropilin-2 genes: identification and distribution of splice variants and soluble isoforms. Genomics 2000 Dec 1;70(2):211-22
  13. Ferrara N
    Vascular endothelial growth factor: basic science and clinical progress. Endocrine reviews 2004 Aug;25(4):581-611
  14. Neufeld G, Kessler O, Herzog Y
    The interaction of Neuropilin-1 and Neuropilin-2 with tyrosine-kinase receptors for VEGF. Advances in experimental medicine and biology 2002;515:81-90
  15. Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G
    Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected]. The Journal of biological chemistry 2000 Jun 16;275(24):18040-5
  16. Kawasaki T, Kitsukawa T, Bekku Y, Matsuda Y, Sanbo M, Yagi T, Fujisawa H
    A requirement for neuropilin-1 in embryonic vessel formation. Development (Cambridge, England) 1999 Nov;126(21):4895-902
  17. Yuan L, Moyon D, Pardanaud L, Breant C, Karkkainen MJ, Alitalo K, Eichmann A
    Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development (Cambridge, England) 2002 Oct;129(20):4797-806
  18. Hutchings H, Ortega N, Plouet J
    Extracellular matrix-bound vascular endothelial growth factor promotes endothelial cell adhesion, migration, and survival through integrin ligation. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 Aug;17(11):1520-2
  19. Hall H, Hubbell JA
    Matrix-bound sixth Ig-like domain of cell adhesion molecule L1 acts as an angiogenic factor by ligating alphavbeta3-integrin and activating VEGF-R2. Microvascular research 2004 Nov;68(3):169-78
  20. Zhang X, Groopman JE, Wang JF
    Extracellular matrix regulates endothelial functions through interaction of VEGFR-3 and integrin alpha5beta1. Journal of cellular physiology 2005 Jan;202(1):205-14
  21. Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi S, Shibuya M
    A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene 1995 Jan 5;10(1):135-47
  22. Sawano A, Takahashi T, Yamaguchi S, Shibuya M
    The phosphorylated 1169-tyrosine containing region of flt-1 kinase (VEGFR-1) is a major binding site for PLCgamma. Biochemical and biophysical research communications 1997 Sep 18;238(2):487-91
  23. 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. The Journal of biological chemistry 1998 Sep 4;273(36):23410-8
  24. Cunningham SA, Waxham MN, Arrate PM, Brock TA
    Interaction of the Flt-1 tyrosine kinase receptor with the p85 subunit of phosphatidylinositol 3-kinase. Mapping of a novel site involved in binding. The Journal of biological chemistry 1995 Sep 1;270(35):20254-7
  25. Dayanir V, Meyer RD, 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. The Journal of biological chemistry 2001 May 25;276(21):17686-92
  26. Pajusola K, Aprelikova O, Pelicci G, Weich H, Claesson-Welsh L, Alitalo K
    Signalling properties of FLT4, a proteolytically processed receptor tyrosine kinase related to two VEGF receptors. Oncogene 1994 Dec;9(12):3545-55
  27. Fournier E, Blaikie P, Rosnet O, Margolis B, Birnbaum D, Borg JP
    Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signaling. Oncogene 1999 Jan 14;18(2):507-14
  28. Wang JF, Zhang X, Groopman JE
    Activation of vascular endothelial growth factor receptor-3 and its downstream signaling promote cell survival under oxidative stress. The Journal of biological chemistry 2004 Jun 25;279(26):27088-97
  29. Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K
    Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. The EMBO journal 2001 Sep 3;20(17):4762-73
  30. Silvestre JS, Tamarat R, Ebrahimian TG, Le-Roux A, Clergue M, Emmanuel F, Duriez M, Schwartz B, Branellec D, Levy BI
    Vascular endothelial growth factor-B promotes in vivo angiogenesis. Circulation research 2003 Jul 25;93(2):114-23
  31. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D
    Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 1996 Apr 15;87(8):3336-43
  32. Clauss M, Weich H, Breier G, Knies U, Rockl W, Waltenberger J, Risau W
    The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. The Journal of biological chemistry 1996 Jul 26;271(30):17629-34
  33. Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, Nakahata T, Shibuya M
    Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 2001 Feb 1;97(3):785-91
  34. Fong GH, Zhang L, Bryce DM, Peng J
    Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development (Cambridge, England) 1999 Jul;126(13):3015-25
  35. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG
    Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nature medicine 2001 May;7(5):575-83
  36. Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, Kliche S, Fellbrich G, Ballmer-Hofer K, Maglione D, Mayr-Beyrle U, Dewerchin M, Dombrowski S, Stanimirovic D, Van Hummelen P, Dehio C, Hicklin DJ, Persico G, Herbert JM, Communi D, Shibuya M, Collen D, Conway EM, Carmeliet P
    Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nature medicine 2003 Jul;9(7):936-43
  37. Alam A, Herault JP, Barron P, Favier B, Fons P, Delesque-Touchard N, Senegas I, Laboudie P, Bonnin J, Cassan C, Savi P, Ruggeri B, Carmeliet P, Bono F, Herbert JM
    Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity. Biochemical and biophysical research communications 2004 Nov 12;324(2):909-15

  1. Zachary I, Gliki G
    Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovascular research 2001 Feb 16;49(3):568-81
  2. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L
    VEGF-receptor signal transduction. Trends in biochemical sciences 2003 Sep;28(9):488-94
  3. de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT
    The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science (New York, N.Y.) 1992 Feb 21;255(5047):989-91
  4. Park JE, Chen HH, Winer J, Houck KA, Ferrara N
    Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. The Journal of biological chemistry 1994 Oct 14;269(41):25646-54
  5. Olofsson B, Korpelainen E, Pepper MS, Mandriota SJ, Aase K, Kumar V, Gunji Y, Jeltsch MM, Shibuya M, Alitalo K, Eriksson U
    Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 1998 Sep 29;95(20):11709-14
  6. Shibuya M
    Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1). The international journal of biochemistry & cell biology 2001 Apr;33(4):409-20
  7. Clauss M
    Molecular biology of the VEGF and the VEGF receptor family. Seminars in thrombosis and hemostasis 2000;26(5):561-9
  8. Pajusola K, Aprelikova O, Korhonen J, Kaipainen A, Pertovaara L, Alitalo R, Alitalo K
    FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer research 1992 Oct 15;52(20):5738-43
  9. Karkkainen MJ, Makinen T, Alitalo K
    Lymphatic endothelium: a new frontier of metastasis research. Nature cell biology 2002 Jan;4(1):E2-5
  10. Saharinen P, Tammela T, Karkkainen MJ, Alitalo K
    Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends in immunology 2004 Jul;25(7):387-95
  11. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M
    Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998 Mar 20;92(6):735-45
  12. Rossignol M, Gagnon ML, Klagsbrun M
    Genomic organization of human neuropilin-1 and neuropilin-2 genes: identification and distribution of splice variants and soluble isoforms. Genomics 2000 Dec 1;70(2):211-22
  13. Ferrara N
    Vascular endothelial growth factor: basic science and clinical progress. Endocrine reviews 2004 Aug;25(4):581-611
  14. Neufeld G, Kessler O, Herzog Y
    The interaction of Neuropilin-1 and Neuropilin-2 with tyrosine-kinase receptors for VEGF. Advances in experimental medicine and biology 2002;515:81-90
  15. Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G
    Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected]. The Journal of biological chemistry 2000 Jun 16;275(24):18040-5
  16. Kawasaki T, Kitsukawa T, Bekku Y, Matsuda Y, Sanbo M, Yagi T, Fujisawa H
    A requirement for neuropilin-1 in embryonic vessel formation. Development (Cambridge, England) 1999 Nov;126(21):4895-902
  17. Yuan L, Moyon D, Pardanaud L, Breant C, Karkkainen MJ, Alitalo K, Eichmann A
    Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development (Cambridge, England) 2002 Oct;129(20):4797-806
  18. Hutchings H, Ortega N, Plouet J
    Extracellular matrix-bound vascular endothelial growth factor promotes endothelial cell adhesion, migration, and survival through integrin ligation. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 Aug;17(11):1520-2
  19. Hall H, Hubbell JA
    Matrix-bound sixth Ig-like domain of cell adhesion molecule L1 acts as an angiogenic factor by ligating alphavbeta3-integrin and activating VEGF-R2. Microvascular research 2004 Nov;68(3):169-78
  20. Zhang X, Groopman JE, Wang JF
    Extracellular matrix regulates endothelial functions through interaction of VEGFR-3 and integrin alpha5beta1. Journal of cellular physiology 2005 Jan;202(1):205-14
  21. Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi S, Shibuya M
    A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene 1995 Jan 5;10(1):135-47
  22. Sawano A, Takahashi T, Yamaguchi S, Shibuya M
    The phosphorylated 1169-tyrosine containing region of flt-1 kinase (VEGFR-1) is a major binding site for PLCgamma. Biochemical and biophysical research communications 1997 Sep 18;238(2):487-91
  23. 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. The Journal of biological chemistry 1998 Sep 4;273(36):23410-8
  24. Cunningham SA, Waxham MN, Arrate PM, Brock TA
    Interaction of the Flt-1 tyrosine kinase receptor with the p85 subunit of phosphatidylinositol 3-kinase. Mapping of a novel site involved in binding. The Journal of biological chemistry 1995 Sep 1;270(35):20254-7
  25. Dayanir V, Meyer RD, 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. The Journal of biological chemistry 2001 May 25;276(21):17686-92
  26. Pajusola K, Aprelikova O, Pelicci G, Weich H, Claesson-Welsh L, Alitalo K
    Signalling properties of FLT4, a proteolytically processed receptor tyrosine kinase related to two VEGF receptors. Oncogene 1994 Dec;9(12):3545-55
  27. Fournier E, Blaikie P, Rosnet O, Margolis B, Birnbaum D, Borg JP
    Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signaling. Oncogene 1999 Jan 14;18(2):507-14
  28. Wang JF, Zhang X, Groopman JE
    Activation of vascular endothelial growth factor receptor-3 and its downstream signaling promote cell survival under oxidative stress. The Journal of biological chemistry 2004 Jun 25;279(26):27088-97
  29. Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K
    Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. The EMBO journal 2001 Sep 3;20(17):4762-73
  30. Silvestre JS, Tamarat R, Ebrahimian TG, Le-Roux A, Clergue M, Emmanuel F, Duriez M, Schwartz B, Branellec D, Levy BI
    Vascular endothelial growth factor-B promotes in vivo angiogenesis. Circulation research 2003 Jul 25;93(2):114-23
  31. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D
    Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 1996 Apr 15;87(8):3336-43
  32. Clauss M, Weich H, Breier G, Knies U, Rockl W, Waltenberger J, Risau W
    The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. The Journal of biological chemistry 1996 Jul 26;271(30):17629-34
  33. Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, Nakahata T, Shibuya M
    Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 2001 Feb 1;97(3):785-91
  34. Fong GH, Zhang L, Bryce DM, Peng J
    Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development (Cambridge, England) 1999 Jul;126(13):3015-25
  35. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG
    Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nature medicine 2001 May;7(5):575-83
  36. Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, Kliche S, Fellbrich G, Ballmer-Hofer K, Maglione D, Mayr-Beyrle U, Dewerchin M, Dombrowski S, Stanimirovic D, Van Hummelen P, Dehio C, Hicklin DJ, Persico G, Herbert JM, Communi D, Shibuya M, Collen D, Conway EM, Carmeliet P
    Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nature medicine 2003 Jul;9(7):936-43
  37. Alam A, Herault JP, Barron P, Favier B, Fons P, Delesque-Touchard N, Senegas I, Laboudie P, Bonnin J, Cassan C, Savi P, Ruggeri B, Carmeliet P, Bono F, Herbert JM
    Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity. Biochemical and biophysical research communications 2004 Nov 12;324(2):909-15

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