Flt4

Summary

Gene Symbol: Flt4
Description: FMS-like tyrosine kinase 4
Alias: AI323512, Chy, Flt-4, VEGFR-3, VEGFR3, vascular endothelial growth factor receptor 3, chylous ascites, receptor protein tyrosine kinase, tyrosine-protein kinase receptor FLT4
Species: mouse
Products:     Flt4

Top Publications

  1. Nilsson I, Rolny C, Wu Y, Pytowski B, Hicklin D, Alitalo K, et al. Vascular endothelial growth factor receptor-3 in hypoxia-induced vascular development. FASEB J. 2004;18:1507-15 pubmed
    ..In addition, sequestering of VEGF receptor-3 ligands reduced vascularization in a manner similar to neutralization of VEGF receptor-3. We conclude that hypoxia-driven vascular development requires the activity of VEGF receptor-3. ..
  2. Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova T, et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J. 2001;20:1223-31 pubmed
    ..These results demonstrate that stimulation of the VEGFR-3 signal transduction pathway is sufficient to induce specifically lymphangiogenesis in vivo. ..
  3. Tammela T, Saaristo A, Lohela M, Morisada T, Tornberg J, Norrmen C, et al. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood. 2005;105:4642-8 pubmed
    ..lymphatic endothelial cells and Ang1 stimulation of these cells resulted in up-regulation of vascular endothelial growth factor receptor 3 (VEGFR-3). Furthermore, a soluble form of VEGFR-3 inhibited the observed lymphatic sprouting...
  4. Wigle J, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell. 1999;98:769-78 pubmed
    ..These findings suggest that Prox1 is a specific and required regulator of the development of the lymphatic system and that the vascular and lymphatic systems develop independently...
  5. Bos F, Caunt M, Peterson Maduro J, Planas Paz L, Kowalski J, Karpanen T, et al. CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circ Res. 2011;109:486-91 pubmed publisher
    ..Insight into the molecular role of CCBE1 is completely lacking, and mouse models for the disease do not exist...
  6. Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, Zambruno G, et al. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med. 2007;204:1431-40 pubmed
    ..Our data suggests that VEGFR-2 signals promote lymphatic vessel enlargement, but unlike in the blood vessels, are not involved in vessel sprouting to generate new lymphatic vessels in vivo. ..
  7. Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D, et al. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol. 2011;13:1202-13 pubmed publisher
    ..Surprisingly, we found that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and ..
  8. Hamrah P, Chen L, Zhang Q, Dana M. Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. Am J Pathol. 2003;163:57-68 pubmed
    ..These data demonstrate, for the first time, the expression of VEGFR-3 and VEGF-C on tissue DC, which implicate a novel potential relationship between lymphangiogenesis and leukocyte trafficking in the eye. ..
  9. Matsumura K, Hirashima M, Ogawa M, Kubo H, Hisatsune H, Kondo N, et al. Modulation of VEGFR-2-mediated endothelial-cell activity by VEGF-C/VEGFR-3. Blood. 2003;101:1367-74 pubmed
    ..Moreover, our findings suggest that the mechanisms underlying AFL4-induced EC dispersion are distinct from those underlying VECD-1-induced dispersion for maintenance of EC integrity. ..
  10. Gordon E, Gale N, Harvey N. Expression of the hyaluronan receptor LYVE-1 is not restricted to the lymphatic vasculature; LYVE-1 is also expressed on embryonic blood vessels. Dev Dyn. 2008;237:1901-9 pubmed publisher
    ..Our data are also the first demonstration, to our knowledge, that the mouse yolk sac is devoid of lymphatic vessels. ..

Detail Information

Publications77

  1. Nilsson I, Rolny C, Wu Y, Pytowski B, Hicklin D, Alitalo K, et al. Vascular endothelial growth factor receptor-3 in hypoxia-induced vascular development. FASEB J. 2004;18:1507-15 pubmed
    ..In addition, sequestering of VEGF receptor-3 ligands reduced vascularization in a manner similar to neutralization of VEGF receptor-3. We conclude that hypoxia-driven vascular development requires the activity of VEGF receptor-3. ..
  2. Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova T, et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J. 2001;20:1223-31 pubmed
    ..These results demonstrate that stimulation of the VEGFR-3 signal transduction pathway is sufficient to induce specifically lymphangiogenesis in vivo. ..
  3. Tammela T, Saaristo A, Lohela M, Morisada T, Tornberg J, Norrmen C, et al. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood. 2005;105:4642-8 pubmed
    ..lymphatic endothelial cells and Ang1 stimulation of these cells resulted in up-regulation of vascular endothelial growth factor receptor 3 (VEGFR-3). Furthermore, a soluble form of VEGFR-3 inhibited the observed lymphatic sprouting...
  4. Wigle J, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell. 1999;98:769-78 pubmed
    ..These findings suggest that Prox1 is a specific and required regulator of the development of the lymphatic system and that the vascular and lymphatic systems develop independently...
  5. Bos F, Caunt M, Peterson Maduro J, Planas Paz L, Kowalski J, Karpanen T, et al. CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circ Res. 2011;109:486-91 pubmed publisher
    ..Insight into the molecular role of CCBE1 is completely lacking, and mouse models for the disease do not exist...
  6. Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, Zambruno G, et al. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med. 2007;204:1431-40 pubmed
    ..Our data suggests that VEGFR-2 signals promote lymphatic vessel enlargement, but unlike in the blood vessels, are not involved in vessel sprouting to generate new lymphatic vessels in vivo. ..
  7. Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D, et al. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol. 2011;13:1202-13 pubmed publisher
    ..Surprisingly, we found that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and ..
  8. Hamrah P, Chen L, Zhang Q, Dana M. Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. Am J Pathol. 2003;163:57-68 pubmed
    ..These data demonstrate, for the first time, the expression of VEGFR-3 and VEGF-C on tissue DC, which implicate a novel potential relationship between lymphangiogenesis and leukocyte trafficking in the eye. ..
  9. Matsumura K, Hirashima M, Ogawa M, Kubo H, Hisatsune H, Kondo N, et al. Modulation of VEGFR-2-mediated endothelial-cell activity by VEGF-C/VEGFR-3. Blood. 2003;101:1367-74 pubmed
    ..Moreover, our findings suggest that the mechanisms underlying AFL4-induced EC dispersion are distinct from those underlying VECD-1-induced dispersion for maintenance of EC integrity. ..
  10. Gordon E, Gale N, Harvey N. Expression of the hyaluronan receptor LYVE-1 is not restricted to the lymphatic vasculature; LYVE-1 is also expressed on embryonic blood vessels. Dev Dyn. 2008;237:1901-9 pubmed publisher
    ..Our data are also the first demonstration, to our knowledge, that the mouse yolk sac is devoid of lymphatic vessels. ..
  11. Karkkainen M, Haiko P, Sainio K, Partanen J, Taipale J, Petrova T, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004;5:74-80 pubmed
    ..Our results indicate that VEGF-C is the paracrine factor essential for lymphangiogenesis, and show that both Vegfc alleles are required for normal lymphatic development. ..
  12. Yuan L, Moyon D, Pardanaud L, Breant C, Karkkainen M, Alitalo K, et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development. 2002;129:4797-806 pubmed
    ..Arteries, veins and larger, collecting lymphatic vessels developed normally, suggesting that neuropilin 2 is selectively required for the formation of small lymphatic vessels and capillaries. ..
  13. Haiko P, Makinen T, Keskitalo S, Taipale J, Karkkainen M, Baldwin M, et al. Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol Cell Biol. 2008;28:4843-50 pubmed publisher
    ..We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the Vegfr3(-/-) embryos, the Vegfc(-/-); Vegfd(-/-) embryos displayed normal blood vasculature after embryonic day 9.5...
  14. Goldman J, Rutkowski J, Shields J, Pasquier M, Cui Y, Schmökel H, et al. Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis. FASEB J. 2007;21:1003-12 pubmed
    ..Our findings demonstrate that cooperative signaling of VEGFR-2 and -3 is necessary for lymphatic migration and proliferation, but VEGFR-3 is redundant with VEGFR-2 for LEC organization into functional capillaries. ..
  15. Guo R, Zhou Q, Proulx S, Wood R, Ji R, Ritchlin C, et al. Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthritis Rheum. 2009;60:2666-76 pubmed publisher
    ..synovial volumes and draining popliteal LN volumes before and after 8 weeks of treatment with vascular endothelial growth factor receptor 3 (VEGFR-3) neutralizing antibody, VEGFR-2 neutralizing antibody, or isotype IgG...
  16. Uhrin P, Zaujec J, Breuss J, Olcaydu D, Chrenek P, Stockinger H, et al. Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood. 2010;115:3997-4005 pubmed publisher
    ..Therefore, interaction of endothelial podoplanin of the developing lymph sac with circulating platelets from the cardinal vein is critical for separating the lymphatic from the blood vascular system...
  17. Karpanen T, Wirzenius M, Makinen T, Veikkola T, Haisma H, Achen M, et al. Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation. Am J Pathol. 2006;169:708-18 pubmed
    ..These results indicate considerable plasticity of lymphatic vessels during the early postnatal period but not thereafter, suggesting that anti-lymphangiogenic therapy can be safely applied in adults. ..
  18. Dumont D, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K, et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science. 1998;282:946-9 pubmed
    ..5. Thus, VEGFR-3 has an essential role in the development of the embryonic cardiovascular system before the emergence of the lymphatic vessels. ..
  19. Wigle J, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn M, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 2002;21:1505-13 pubmed
    ..On the basis of our findings, we propose that a blood vascular phenotype is the default fate of budding embryonic venous endothelial cells; upon expression of Prox1, these budding cells adopt a lymphatic vasculature phenotype. ..
  20. Pytowski B, Goldman J, Persaud K, Wu Y, Witte L, Hicklin D, et al. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst. 2005;97:14-21 pubmed
    New lymphatic growth may contribute to tumor metastasis. Activation of vascular endothelial growth factor receptor 3 (VEGFR-3) by its ligands VEGF-C and -D is necessary for embryonic and tumor lymphangiogenesis...
  21. Ichise T, Yoshida N, Ichise H. H-, N- and Kras cooperatively regulate lymphatic vessel growth by modulating VEGFR3 expression in lymphatic endothelial cells in mice. Development. 2010;137:1003-13 pubmed publisher
    ..The close link between Ras and VEGFR3 in vitro is consistent with the result that Ras knockout and transgenic alleles are genetic modifiers in lymphatic ..
  22. Zhang L, Zhou F, Han W, Shen B, Luo J, Shibuya M, et al. VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis. Cell Res. 2010;20:1319-31 pubmed publisher
    ..two genetically modified mouse models in this study, targeting the coding region for the ligand-binding domain (Vegfr3(?LBD)) or the tyrosine kinase domain with an inactivation point mutation (Vegfr3(TKmut))...
  23. Sabine A, Agalarov Y, Maby El Hajjami H, Jaquet M, Hägerling R, Pollmann C, et al. Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation. Dev Cell. 2012;22:430-45 pubmed publisher
    ..Our results also provide molecular insights into the role of endothelial cell identity in the regulation of vascular mechanotransduction. ..
  24. Kulkarni R, Greenberg J, Akeson A. NFATc1 regulates lymphatic endothelial development. Mech Dev. 2009;126:350-65 pubmed publisher
    ..In reporter assays, NFATc1 activated lymphatic specific gene promoters. These results demonstrate the role of calcineurin-NFAT pathway in lymphangiogenesis and suggest that NFATc1 is the principle NFAT involved. ..
  25. Kulkarni R, Herman A, Ikegami M, Greenberg J, Akeson A. Lymphatic ontogeny and effect of hypoplasia in developing lung. Mech Dev. 2011;128:29-40 pubmed publisher
    ..Surfactant synthesis was unaffected. Together, these data demonstrate that lung lymphatics develop autonomously and that pulmonary lymphatic hypoplasia is detrimental to survival of the neonate due to impaired lung fluid clearance. ..
  26. Kukk E, Lymboussaki A, Taira S, Kaipainen A, Jeltsch M, Joukov V, et al. VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development. 1996;122:3829-37 pubmed
    ..The recombinant mouse VEGF-C protein was secreted from transfected cells as VEGFR-3 (Flt4) binding polypeptides of 30-32x10(3) Mr and 22-23x10(3) Mr which preferentially stimulated the autophosphorylation ..
  27. Tammela T, Zarkada G, Wallgard E, Murtomäki A, Suchting S, Wirzenius M, et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 2008;454:656-60 pubmed publisher
    ..Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors. ..
  28. Benedito R, Rocha S, Woeste M, Zamykal M, Radtke F, Casanovas O, et al. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature. 2012;484:110-4 pubmed publisher
    ..By contrast, VEGFR3, the main receptor for VEGF-C, was strongly modulated by Notch...
  29. Makinen T, Adams R, Bailey J, Lu Q, Ziemiecki A, Alitalo K, et al. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev. 2005;19:397-410 pubmed
    ..Our studies define ephrinB2 as an essential regulator of lymphatic development and indicate that interactions with PDZ domain effectors are required to mediate its functions. ..
  30. Planas Paz L, Strilic B, Goedecke A, Breier G, Fassler R, Lammert E. Mechanoinduction of lymph vessel expansion. EMBO J. 2012;31:788-804 pubmed publisher
    ..reduces the length of LECs, decreases tyrosine phosphorylation of vascular endothelial growth factor receptor-3 (VEGFR3), and inhibits LEC proliferation...
  31. Bazigou E, Xie S, Chen C, Weston A, Miura N, Sorokin L, et al. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell. 2009;17:175-86 pubmed publisher
    ..Our findings reveal an important role for integrin-alpha9 signaling during lymphatic valve morphogenesis and implicate it as a candidate gene for primary lymphedema caused by valve defects...
  32. Kubo H, Cao R, Brakenhielm E, Makinen T, Cao Y, Alitalo K. Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci U S A. 2002;99:8868-73 pubmed
    ..Because increased expression of FGF-2 and VEGF-C has been associated with lymphatic metastasis, our results provide a potential strategy for the inhibition of lymphatic metastasis in cancer therapy. ..
  33. Petrova T, Karpanen T, Norrmen C, Mellor R, Tamakoshi T, Finegold D, et al. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med. 2004;10:974-81 pubmed
    ..individuals with LD and in mice heterozygous for Foxc2 and for the gene encoding lymphatic endothelial receptor, Vegfr3 (also known as Flt4)...
  34. Mishima K, Watabe T, Saito A, Yoshimatsu Y, Imaizumi N, Masui S, et al. Prox1 induces lymphatic endothelial differentiation via integrin alpha9 and other signaling cascades. Mol Biol Cell. 2007;18:1421-9 pubmed
    ..preferentially migrated toward VEGF-C via up-regulation of the expression of integrin alpha9 and VEGF receptor 3 (VEGFR3)...
  35. Baldwin M, Catimel B, Nice E, Roufail S, Hall N, Stenvers K, et al. The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man. J Biol Chem. 2001;276:19166-71 pubmed
    ..This suggests that VEGF-D and VEGFR-3 may play a role in establishing vessels of the skin by a paracrine mechanism. Our study of receptor specificity suggests that VEGF-D may have different biological functions in mouse and man. ..
  36. Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh V, Fang G, Dumont D, et al. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A. 1995;92:3566-70 pubmed
    We have recently cloned the human fms-like tyrosine kinase 4 gene FLT4, whose protein product is related to two vascular endothelial growth factor receptors FLT1 and KDR/FLK1...
  37. Kim K, Sung H, Koh G. Lymphatic development in mouse small intestine. Dev Dyn. 2007;236:2020-5 pubmed
    ..development by immunostaining with recently discovered molecular markers for lymphatic endothelial cells: LYVE-1, VEGFR3, Prox-1, and podoplanin...
  38. Fong G, Rossant J, Gertsenstein M, Breitman M. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 1995;376:66-70 pubmed
    ..We suggest that the Flt-1 signalling pathway may regulate normal endothelial cell-cell or cell-matrix interactions during vascular development. ..
  39. Karkkainen M, Saaristo A, Jussila L, Karila K, Lawrence E, Pajusola K, et al. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A. 2001;98:12677-82 pubmed
    ..Like the human patients, the lymphedema (Chy) mice have an inactivating Vegfr3 mutation in their germ line, and swelling of the limbs because of hypoplastic cutaneous, but not visceral, ..
  40. Khandekar M, Brandt W, Zhou Y, Dagenais S, Glover T, Suzuki N, et al. A Gata2 intronic enhancer confers its pan-endothelia-specific regulation. Development. 2007;134:1703-12 pubmed
    ..Thus, GATA-2 is expressed early in lymphatic, cardiac and blood vascular endothelial cells, and the pan-endothelium-specific expression of Gata2 is controlled by a discrete intronic enhancer. ..
  41. Xu Y, Yuan L, Mak J, Pardanaud L, Caunt M, Kasman I, et al. Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J Cell Biol. 2010;188:115-30 pubmed publisher
    ..Thus, interaction between Nrp2 and VEGFR3 mediates proper lymphatic vessel sprouting in response to VEGF-C.
  42. Srinivasan R, Oliver G. Prox1 dosage controls the number of lymphatic endothelial cell progenitors and the formation of the lymphovenous valves. Genes Dev. 2011;25:2187-97 pubmed publisher
    ..This is the first report describing the molecular mechanism controlling lymphovenous communication. ..
  43. Shalaby F, Rossant J, Yamaguchi T, Gertsenstein M, Wu X, Breitman M, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376:62-6 pubmed
    ..These results indicate that Flk-1 is essential for yolk-sac blood-island formation and vasculogenesis in the mouse embryo. ..
  44. Norrmen C, Ivanov K, Cheng J, Zangger N, Delorenzi M, Jaquet M, et al. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J Cell Biol. 2009;185:439-57 pubmed publisher
    ..As damage to collecting vessels is a major cause of lymphatic dysfunction in humans, our results suggest that FOXC2 and NFATc1 are potential targets for therapeutic intervention. ..
  45. Yuen D, Pytowski B, Chen L. Combined blockade of VEGFR-2 and VEGFR-3 inhibits inflammatory lymphangiogenesis in early and middle stages. Invest Ophthalmol Vis Sci. 2011;52:2593-7 pubmed publisher
    ..The purpose of this study was to investigate whether there is a time window for therapeutic intervention of corneal LG and whether a combined blockade of VEGFR-2 and VEGFR-3 effectively suppresses early-, middle-, or late-stage LG...
  46. Kawahara M, Wu Q, Kono T. Involvement of insulin-like growth factor 2 in angiogenic factor transcription in Bi-maternal mouse conceptuses. J Reprod Dev. 2010;56:79-85 pubmed
    ..clarify this, we performed quantitative gene expression analysis for representative angiogenic factors-Vegf, Flt1, Flt4, Flk1, Ang1, Ang2, Tie1, and Tie2-for 3 types of bi-maternal conceptuses containing genomes with non-growing (ng) ..
  47. Langen U, Pitulescu M, Kim J, Enriquez Gasca R, Sivaraj K, Kusumbe A, et al. Cell-matrix signals specify bone endothelial cells during developmental osteogenesis. Nat Cell Biol. 2017;19:189-201 pubmed publisher
    ..Our work outlines fundamental principles of vessel formation and endothelial cell differentiation in the developing skeletal system. ..
  48. Rutkowski J, Ihm J, Lee S, Kilarski W, Greenwood V, Pasquier M, et al. VEGFR-3 neutralization inhibits ovarian lymphangiogenesis, follicle maturation, and murine pregnancy. Am J Pathol. 2013;183:1596-1607 pubmed publisher
    ..We used systemic delivery of mF4-31C1, a specific antagonist vascular endothelial growth factor receptor 3 (VEGFR-3) antibody to block lymphangiogenesis in mice...
  49. Hamada K, Oike Y, Takakura N, Ito Y, Jussila L, Dumont D, et al. VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis. Blood. 2000;96:3793-800 pubmed
    ..This indicates that elaborated control through VEGFR-3 signaling is critical in vasculoangiogenesis and hematopoiesis. (Blood. 2000;96:3793-3800) ..
  50. Calvo C, Fontaine R, Soueid J, Tammela T, Makinen T, Alfaro Cervello C, et al. Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis. Genes Dev. 2011;25:831-44 pubmed publisher
    ..b>Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated ..
  51. Cursiefen C, Ikeda S, Nishina P, Smith R, Ikeda A, Jackson D, et al. Spontaneous corneal hem- and lymphangiogenesis in mice with destrin-mutation depend on VEGFR3 signaling. Am J Pathol. 2005;166:1367-77 pubmed
    ..Finally, in this novel mouse model, a blocking anti-VEGFR3 antibody significantly inhibited not only lymph- but also hemangiogenesis...
  52. Ho L, van Dijk M, Chye S, Messerschmidt D, Chng S, Ong S, et al. ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. Science. 2017;357:707-713 pubmed publisher
    ..The ELA-APLNR signaling axis may offer a new paradigm for the treatment of common pregnancy-related complications, including PE. ..
  53. Jang J, Choi S, Park I, Park D, Choe K, Kim P, et al. VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis. EMBO Mol Med. 2017;9:750-769 pubmed publisher
    ..Our genetic depletion experiments revealed that VEGFR2, but not VEGFR3, is indispensable for maintenance of thyroid vascular integrity...
  54. Munger S, Geng X, Srinivasan R, Witte M, Paul D, Simon A. Segregated Foxc2, NFATc1 and Connexin expression at normal developing venous valves, and Connexin-specific differences in the valve phenotypes of Cx37, Cx43, and Cx47 knockout mice. Dev Biol. 2016;412:173-90 pubmed publisher
    ..The partition of Foxc2 and NFATc1 expression at VV leaflets makes it unlikely that these factors directly cooperate during the leaflet elongation stage of VV development. ..
  55. Rutkowski J, Markhus C, Gyenge C, Alitalo K, Wiig H, Swartz M. Dermal collagen and lipid deposition correlate with tissue swelling and hydraulic conductivity in murine primary lymphedema. Am J Pathol. 2010;176:1122-9 pubmed publisher
    ..Functionally, this resulted in a greatly increased dermal hydraulic conductivity in K14-VEGFR3-Ig, but not Chy, mice...
  56. Niessen K, Zhang G, Ridgway J, Chen H, Yan M. ALK1 signaling regulates early postnatal lymphatic vessel development. Blood. 2010;115:1654-61 pubmed publisher
    ..simultaneous inhibition of ALK1 pathway increases apoptosis in lymphatic vessels caused by blockade of VEGFR3 signaling...
  57. Berggreen E, Haug S, Mkonyi L, Bletsa A. Characterization of the dental lymphatic system and identification of cells immunopositive to specific lymphatic markers. Eur J Oral Sci. 2009;117:34-42 pubmed publisher
    ..In inflamed pulp these cells were not observed. Macrophages are suggested to contribute directly to the formation of lymphatic vessels after pulp exposure. ..
  58. Bi W, Drake C, Schwarz J. The transcription factor MEF2C-null mouse exhibits complex vascular malformations and reduced cardiac expression of angiopoietin 1 and VEGF. Dev Biol. 1999;211:255-67 pubmed
  59. Ikomi F, Kawai Y, Nakayama J, Ogiwara N, Sasaki K, Mizuno R, et al. Critical roles of VEGF-C-VEGF receptor 3 in reconnection of the collecting lymph vessels in mice. Microcirculation. 2008;15:591-603 pubmed publisher
    ..lymph vessel significantly increased the rate of the reconnected lymph vessels, whereas additional treatment with Flt4/Fc chimera protein significantly reduced the rate of the reconnected ones...
  60. Gauvrit S, Philippe J, Lesage M, Tjwa M, Godin I, Germain S. The role of RNA interference in the developmental separation of blood and lymphatic vasculature. Vasc Cell. 2014;6:9 pubmed publisher
  61. Galland F, Karamysheva A, Mattei M, Rosnet O, Marchetto S, Birnbaum D. Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase gene. Genomics. 1992;13:475-8 pubmed
    ..The gene was named FLT4. Cosmid clones of the mouse Flt4 gene were isolated...
  62. Finnerty H, Kelleher K, Morris G, Bean K, Merberg D, Kriz R, et al. Molecular cloning of murine FLT and FLT4. Oncogene. 1993;8:2293-8 pubmed
    ..A novel RTK, called FLT4, and the murine homologue of FLT were found, and their PCR fragment sequences were used to isolate larger cDNA ..
  63. Sato T, Paquet Fifield S, Harris N, Roufail S, Turner D, Yuan Y, et al. VEGF-D promotes pulmonary oedema in hyperoxic acute lung injury. J Pathol. 2016;239:152-61 pubmed publisher
    ..2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. ..
  64. Dartsch N, Schulte D, Hägerling R, Kiefer F, Vestweber D. Fusing VE-cadherin to ?-catenin impairs fetal liver hematopoiesis and lymph but not blood vessel formation. Mol Cell Biol. 2014;34:1634-48 pubmed publisher
    ..Thus, stabilizing endothelial cell contacts by a covalent link between VE-cadherin and ?-catenin affects recruitment of hematopoietic progenitors into the fetal liver and the development of lymph but not blood vessels. ..
  65. Kajiya K, Sawane M, Huggenberger R, Detmar M. Activation of the VEGFR-3 pathway by VEGF-C attenuates UVB-induced edema formation and skin inflammation by promoting lymphangiogenesis. J Invest Dermatol. 2009;129:1292-8 pubmed publisher
  66. Anderson K, Pan L, Yang X, Hughes V, Walls J, Dominguez M, et al. Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor. Proc Natl Acad Sci U S A. 2011;108:2807-12 pubmed publisher
    ..These results represent a unique function attributed to a long N-terminal group B-type G protein-coupled receptor in a mammalian system. ..
  67. Flister M, Wilber A, Hall K, Iwata C, Miyazono K, Nisato R, et al. Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. Blood. 2010;115:418-29 pubmed publisher
    ..This, in turn, enhances the responsiveness of preexisting lymphatic endothelium to VEGFR-3 binding factors, VEGF-C and VEGF-D, ultimately resulting in robust lymphangiogenesis. ..
  68. Bowles J, Secker G, Nguyen C, Kazenwadel J, Truong V, Frampton E, et al. Control of retinoid levels by CYP26B1 is important for lymphatic vascular development in the mouse embryo. Dev Biol. 2014;386:25-33 pubmed publisher
    ..Our studies identify a genetic pathway that underpins the architecture of the developing lymphatics and define CYP26B1 as a novel modulator of lymphatic vascular patterning. ..
  69. Brouillard P, Boon L, Vikkula M. Genetics of lymphatic anomalies. J Clin Invest. 2014;124:898-904 pubmed publisher
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