Vascular Endothelial Growth Factor A (VEGF-A) Is Involved in Guidance of VEGF Receptor-Positive Cells to the Anterior Portion of Early Embryos

ABSTRACT The hemangioblast in the mesoderm gives rise to both angioblasts and hematopoietic stem cells. The movement of hemangioblast precursor cells in the fetal trunk is a critical event in early embryogenesis. Vascular endothelial growth factor (VEGF) signaling is likely involved in this migration given the partial disturbance of VEGF receptor (VEGFR)-positive cell accumulation and migration in VEGFR2 null mice or mice with a truncated VEGFR1. However, it is not clear how the VEGF system regulates this migration or its direction. We show here that the expression of VEGF-A is dominant in the anterior portion of the embryo, whereas VEGFR1 and VEGFR2 are expressed in the posterior portion of the embryo. An inhibitor of VEGFR kinase blocked the migration of VEGFR-positive cells in a whole-embryo culture system. In addition, VEGFR-positive cells migrated toward a VEGFR1- or VEGFR2-specific ligand in vitro. Furthermore, VEGFR-positive cells derived from wild-type or VEGFR2+/− mice moved rapidly anteriorly, whereas cells derived from VEGFR2+/− mice carrying a truncated VEGFR1 [VEGFR1(TM-TK)−/−] migrated little when injected into wild-type mice. These results suggest that the VEGF-A protein concentrated in the anterior region plays an important role in the guidance of VEGFR-positive cells from the posterior portion to the head region by interacting with VEGFR in the mouse embryo.

[1]  Kenji Nakamura,et al.  Membrane Fixation of Vascular Endothelial Growth Factor Receptor 1 Ligand-Binding Domain Is Important for Vasculogenesis and Angiogenesis in Mice , 2005, Molecular and Cellular Biology.

[2]  Kenji Nakamura,et al.  Membrane Fixation of Vascular Endothelial Growth Factor Receptor 1 Ligand-Binding Domain Is Important for Vasculogenesis and Angiogenesis in Mice , 2005, Molecular and Cellular Biology.

[3]  J. Partanen,et al.  Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins , 2004, Nature Immunology.

[4]  J. Partanen,et al.  Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins , 2004, Nature Immunology.

[5]  C. Peschle,et al.  Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor. , 2003, Blood.

[6]  C. Peschle,et al.  Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor. , 2003, Blood.

[7]  糸川 高史.  Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling , 2003 .

[8]  M. Shibuya,et al.  MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. , 2002, Cancer cell.

[9]  M. Shibuya,et al.  MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. , 2002, Cancer cell.

[10]  S. Rafii,et al.  Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment , 2002, Nature Medicine.

[11]  S. Rafii,et al.  Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment , 2002, Nature Medicine.

[12]  Eric Johnson,et al.  Developmental Control of Blood Cell Migration by the Drosophila VEGF Pathway , 2002, Cell.

[13]  Eric Johnson,et al.  Developmental Control of Blood Cell Migration by the Drosophila VEGF Pathway , 2002, Cell.

[14]  M. Shibuya,et al.  Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling. , 2002, Molecular cancer therapeutics.

[15]  N. Ferrara,et al.  The role of VEGF in normal and neoplastic hematopoiesis , 2002, Journal of Molecular Medicine.

[16]  N. Ferrara,et al.  The role of VEGF in normal and neoplastic hematopoiesis , 2002, Journal of Molecular Medicine.

[17]  M. Shibuya,et al.  Antiangiogenic Effect by SU 5416 Is Partly Attributable to Inhibition of Flt-1 Receptor Signaling 1 , 2002 .

[18]  P. Rørth,et al.  Guidance of Cell Migration by the Drosophila PDGF/VEGF Receptor , 2001, Cell.

[19]  P. Rørth,et al.  Guidance of Cell Migration by the Drosophila PDGF/VEGF Receptor , 2001, Cell.

[20]  K. Alitalo,et al.  Vascular Endothelial Growth Factor-B–Deficient Mice Display an Atrial Conduction Defect , 2001, Circulation.

[21]  K. Alitalo,et al.  Vascular Endothelial Growth Factor-B–Deficient Mice Display an Atrial Conduction Defect , 2001, Circulation.

[22]  M. Shibuya,et al.  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 , 2001, The EMBO journal.

[23]  M. Shibuya,et al.  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 , 2001, The EMBO journal.

[24]  Till Acker,et al.  Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions , 2001, Nature Medicine.

[25]  Till Acker,et al.  Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions , 2001, Nature Medicine.

[26]  M. Shibuya.  Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. , 2001, Cell structure and function.

[27]  M. Shibuya.  Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. , 2001, Cell structure and function.

[28]  S. Nishikawa,et al.  Origin of Hematopoietic Progenitors during Embryogenesis , 2001, International reviews of immunology.

[29]  S. Nishikawa,et al.  Origin of Hematopoietic Progenitors during Embryogenesis , 2001, International reviews of immunology.

[30]  M. Persico.  Placenta Growth Factor , 2001 .

[31]  Jun Yamashita,et al.  Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors , 2000, Nature.

[32]  Jun Yamashita,et al.  Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors , 2000, Nature.

[33]  N. Ferrara,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 , 2000, The EMBO journal.

[34]  N. Ferrara,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 , 2000, The EMBO journal.

[35]  T. Noda,et al.  A Role for Hematopoietic Stem Cells in Promoting Angiogenesis , 2000, Cell.

[36]  T. Noda,et al.  A Role for Hematopoietic Stem Cells in Promoting Angiogenesis , 2000, Cell.

[37]  S. Aparício,et al.  Eomesodermin is required for mouse trophoblast development and mesoderm formation , 2000, Nature.

[38]  S. Aparício,et al.  Eomesodermin is required for mouse trophoblast development and mesoderm formation , 2000, Nature.

[39]  G. Kay,et al.  Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. , 2000, Circulation research.

[40]  G. Kay,et al.  Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. , 2000, Circulation research.

[41]  A. Nagy,et al.  The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo. , 1999, Development.

[42]  A. Nagy,et al.  The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo. , 1999, Development.

[43]  J. Peng,et al.  Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. , 1999, Development.

[44]  J. Peng,et al.  Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. , 1999, Development.

[45]  M. Shibuya,et al.  VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells , 1999, Oncogene.

[46]  M. Shibuya,et al.  VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells , 1999, Oncogene.

[47]  A. Ullrich,et al.  SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. , 1999, Cancer research.

[48]  A. Ullrich,et al.  SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. , 1999, Cancer research.

[49]  M. Shibuya,et al.  Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[50]  M. Shibuya,et al.  Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[51]  T. Noda,et al.  Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[52]  T. Noda,et al.  Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[53]  K. Shitara,et al.  Significant expression of vascular endothelial growth factor/vascular permeability factor in mouse ascites tumors. , 1998, Cancer research.

[54]  K. Shitara,et al.  Significant expression of vascular endothelial growth factor/vascular permeability factor in mouse ascites tumors. , 1998, Cancer research.

[55]  S. Nishikawa,et al.  Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. , 1998, Development.

[56]  S. Nishikawa,et al.  Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. , 1998, Development.

[57]  M. Shibuya,et al.  Genomic organization of the flt-1 gene encoding for vascular endothelial growth factor (VEGF) receptor-1 suggests an intimate evolutionary relationship between the 7-Ig and the 5-Ig tyrosine kinase receptors. , 1998, Gene.

[58]  M. Shibuya,et al.  Genomic organization of the flt-1 gene encoding for vascular endothelial growth factor (VEGF) receptor-1 suggests an intimate evolutionary relationship between the 7-Ig and the 5-Ig tyrosine kinase receptors. , 1998, Gene.

[59]  K. Alitalo,et al.  Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[60]  K. Alitalo,et al.  Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[61]  R. Behringer,et al.  Mouse gastrulation: the formation of a mammalian body plan , 1997, Mechanisms of Development.

[62]  R. Behringer,et al.  Mouse gastrulation: the formation of a mammalian body plan , 1997, Mechanisms of Development.

[63]  M. Shibuya,et al.  The phosphorylated 1169-tyrosine containing region of flt-1 kinase (VEGFR-1) is a major binding site for PLCgamma. , 1997, Biochemical and biophysical research communications.

[64]  M. Shibuya,et al.  The phosphorylated 1169-tyrosine containing region of flt-1 kinase (VEGFR-1) is a major binding site for PLCgamma. , 1997, Biochemical and biophysical research communications.

[65]  W. Risau,et al.  Mechanisms of angiogenesis , 1997, Nature.

[66]  W. Risau,et al.  Mechanisms of angiogenesis , 1997, Nature.

[67]  N. Ferrara,et al.  The biology of vascular endothelial growth factor. , 1997, Endocrine reviews.

[68]  N. Ferrara,et al.  The biology of vascular endothelial growth factor. , 1997, Endocrine reviews.

[69]  G. Breier,et al.  The Vascular Endothelial Growth Factor Receptor Flt-1 Mediates Biological Activities , 1996, The Journal of Biological Chemistry.

[70]  A. Mantovani,et al.  Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. , 1996, Blood.

[71]  A. Mantovani,et al.  Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. , 1996, Blood.

[72]  Lieve Moons,et al.  Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele , 1996, Nature.

[73]  Lieve Moons,et al.  Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele , 1996, Nature.

[74]  Kenneth J. Hillan,et al.  Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene , 1996, Nature.

[75]  Kenneth J. Hillan,et al.  Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene , 1996, Nature.

[76]  K. Alitalo,et al.  Vascular endothelial growth factor B, a novel growth factor for endothelial cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[77]  K. Alitalo,et al.  Vascular endothelial growth factor B, a novel growth factor for endothelial cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[78]  W. Wood,et al.  Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[79]  W. Wood,et al.  Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[80]  K. Alitalo,et al.  A novel vascular endothelial growth factor, VEGF‐C, is a ligand for the Flt4 (VEGFR‐3) and KDR (VEGFR‐2) receptor tyrosine kinases. , 1996, The EMBO journal.

[81]  K. Alitalo,et al.  A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. , 1996, The EMBO journal.

[82]  Janet Rossant,et al.  Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice , 1995, Nature.

[83]  J. Rossant,et al.  Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium , 1995, Nature.

[84]  J. Rossant,et al.  Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium , 1995, Nature.

[85]  Janet Rossant,et al.  Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice , 1995, Nature.

[86]  K. Alitalo,et al.  Endothelial receptor tyrosine kinases involved in angiogenesis , 1995, The Journal of cell biology.

[87]  K. Alitalo,et al.  Endothelial receptor tyrosine kinases involved in angiogenesis , 1995, The Journal of cell biology.

[88]  K. Alitalo,et al.  Vascularization of the mouse embryo: A study of flk‐1, tek, tie, and vascular endothelial growth factor expression during development , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.

[89]  K. Alitalo,et al.  Vascularization of the mouse embryo: A study of flk‐1, tek, tie, and vascular endothelial growth factor expression during development , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.

[90]  M. Shibuya,et al.  A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. , 1995, Oncogene.

[91]  M. Shibuya,et al.  A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. , 1995, Oncogene.

[92]  P. Tam,et al.  Regionalisation of cell fate and morphogenetic movement of the mesoderm during mouse gastrulation. , 1995, Developmental genetics.

[93]  P. Tam,et al.  Regionalisation of cell fate and morphogenetic movement of the mesoderm during mouse gastrulation. , 1995, Developmental genetics.

[94]  J. Winer,et al.  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. , 1994, The Journal of biological chemistry.

[95]  J. Winer,et al.  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. , 1994, The Journal of biological chemistry.

[96]  M. Shibuya,et al.  A new communication system between hepatocytes and sinusoidal endothelial cells in liver through vascular endothelial growth factor and Flt tyrosine kinase receptor family (Flt-1 and KDR/Flk-1). , 1994, Oncogene.

[97]  M. Shibuya,et al.  A new communication system between hepatocytes and sinusoidal endothelial cells in liver through vascular endothelial growth factor and Flt tyrosine kinase receptor family (Flt-1 and KDR/Flk-1). , 1994, Oncogene.

[98]  K. Alitalo,et al.  The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells , 1993, The Journal of experimental medicine.

[99]  K. Alitalo,et al.  The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells , 1993, The Journal of experimental medicine.

[100]  R. Kendall,et al.  Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[101]  R. Kendall,et al.  Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[102]  T. Quinn,et al.  Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[103]  T. Quinn,et al.  Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[104]  C. Marcelle,et al.  Two molecules related to the VEGF receptor are expressed in early endothelial cells during avian embryonic development , 1993, Mechanisms of Development.

[105]  C. Marcelle,et al.  Two molecules related to the VEGF receptor are expressed in early endothelial cells during avian embryonic development , 1993, Mechanisms of Development.

[106]  D. Dimitrov,et al.  Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. , 1992, Biochemical and biophysical research communications.

[107]  D. Dimitrov,et al.  Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. , 1992, Biochemical and biophysical research communications.

[108]  P. Tam,et al.  The somitogenetic potential of cells in the primitive streak and the tail bud of the organogenesis-stage mouse embryo. , 1992, Development.

[109]  P. Tam,et al.  The somitogenetic potential of cells in the primitive streak and the tail bud of the organogenesis-stage mouse embryo. , 1992, Development.

[110]  J. Winer,et al.  Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. , 1992, The Journal of clinical investigation.

[111]  J. Winer,et al.  Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. , 1992, The Journal of clinical investigation.

[112]  R. Pedersen,et al.  Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. , 1991, Development.

[113]  R. Pedersen,et al.  Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. , 1991, Development.

[114]  N. Copeland,et al.  A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[115]  N. Copeland,et al.  A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[116]  G. Viglietto,et al.  Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[117]  G. Viglietto,et al.  Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[118]  M. Shibuya,et al.  Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. , 1990, Oncogene.

[119]  M. Shibuya,et al.  Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. , 1990, Oncogene.

[120]  N. Nakatsuji,et al.  An ECM substratum allows mouse mesodermal cells isolated from the primitive streak to exhibit motility similar to that inside the embryo and reveals a deficiency in the T/T mutant cells. , 1987, Development.

[121]  N. Nakatsuji,et al.  An ECM substratum allows mouse mesodermal cells isolated from the primitive streak to exhibit motility similar to that inside the embryo and reveals a deficiency in the T/T mutant cells. , 1987, Development.

[122]  R. Beddington,et al.  The formation of mesodermal tissues in the mouse embryo during gastrulation and early organogenesis. , 1987, Development.

[123]  R. Beddington,et al.  The formation of mesodermal tissues in the mouse embryo during gastrulation and early organogenesis. , 1987, Development.