Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Endothelial cells and VEGF in vascular development

Abstract

The intricate patterning processes that establish the complex vascular system during development depend on a combination of intrinsic pre-patterning and extrinsic responses to environmental parameters. Mutational studies in mice and fish have shown that the vascular system is highly sensitive to genetic disruption and have identified potential targets for therapeutic interventions. New insights into non-vascular roles of vascular endothelial growth factor and the requirement for endothelial cells in adult organs and stem-cell niches highlight possible side effects of anti-angiogenic therapy and the need for new targets.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Murine embryonic vasculature.
Figure 2: Formation of a functional circulation from endothelial progenitors.
Figure 3: Vascular development along the mammalian body axis.
Figure 4: Formation of the fetal vasculature in the chorio-allantoic placenta.
Figure 5: Endothelial cells provide a niche for haematopoietic stem cells (HSCs).

References

  1. Carmeliet, P. Angiogenesis in health and disease. Nature Med. 9, 653–660 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Rossant, J. & Howard, L. Signaling pathways in vascular development. Annu. Rev. Cell Dev. Biol. 18, 541–573 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Bikfalvi, A. & Bicknell, R. Recent advances in angiogenesis, anti-angiogenesis and vascular targeting. Trends Pharmacol. Sci. 23, 576–582 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Thurston, G. Role of angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis. Cell Tissue Res. 314, 61–68 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Betsholtz, C., Lindblom, P. & Gerhardt, H. Role of pericytes in vascular morphogenesis. EXS 115–125 (2005).

  6. Lebrin, F., Deckers, M., Bertolino, P. & Ten Dijke, P. TGF-M receptor function in the endothelium. Cardiovasc. Res. 65, 599–608 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Shalaby, F. et al. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 89, 981–990 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Ema, M. & Rossant, J. Cell fate decisions in early blood vessel formation. Trends Cardiovasc. Med. 13, 254–259 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Choi, K., Kennedy, M., Kazarov, A., Papadimitriou, J. C. & Keller, G. A common precursor for hematopoietic and endothelial cells. Development 125, 725–732 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Chung, Y. S. et al. Lineage analysis of the hemangioblast as defined by FLK1 and SCL expression. Development 129, 5511–5520 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Huber, T. L., Kouskoff, V., Fehling, H. J., Palis, J. & Keller, G. Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature 432, 625–630 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  15. Yamashita, J. et al. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408, 92–96 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Ema, M. et al. Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse. Genes Dev. 17, 380–393 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schroeder, T. et al. Recombination signal sequence-binding protein Jg alters mesodermal cell fate decisions by suppressing cardiomyogenesis. Proc. Natl Acad. Sci. USA 100, 4018–4023 (2003).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jiang, Y. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41–49 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Minasi, M. G. et al. The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues. Development 129, 2773–2783 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Kinder, S. J., Loebel, D. A. & Tam, P. P. Allocation and early differentiation of cardiovascular progenitors in the mouse embryo. Trends Cardiovasc. Med. 11, 177–184 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Ferkowicz, M. J. et al. CD41 expression defines the onset of primitive and definitive hematopoiesis in the murine embryo. Development 130, 4393–4403 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Jones, E. A. et al. Dynamic in vivo imaging of postimplantation mammalian embryos using whole embryo culture. Genesis 34, 228–235 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Ramirez-Bergeron, D. L. et al. Hypoxia affects mesoderm and enhances hemangioblast specification during early development. Development 131, 4623–4634 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. le Noble, F. et al. Flow regulates arterial-venous differentiation in the chick embryo yolk sac. Development 131, 361–375 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Adams, R. H. et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 13, 295–306 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, H. U., Chen, Z. F. & Anderson, D. J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741–753 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Gerety, S. S., Wang, H. U., Chen, Z. F. & Anderson, D. J. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol. Cell 4, 403–414 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Herzog, Y., Guttmann-Raviv, N. & Neufeld, G. Segregation of arterial and venous markers in subpopulations of blood islands before vessel formation. Dev. Dyn. 232, 1047–1055 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Zhong, T. P., Childs, S., Leu, J. P. & Fishman, M. C. Gridlock signalling pathway fashions the first embryonic artery. Nature 414, 216–220 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  30. Moyon, D., Pardanaud, L., Yuan, L., Breant, C. & Eichmann, A. Plasticity of endothelial cells during arterial-venous differentiation in the avian embryo. Development 128, 3359–3370 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Isogai, S., Lawson, N. D., Torrealday, S., Horiguchi, M. & Weinstein, B. M. Angiogenic network formation in the developing vertebrate trunk. Development 130, 5281–5290 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Lawson, N. D. et al. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128, 3675–3683 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Zhong, T. P., Rosenberg, M., Mohideen, M. A., Weinstein, B. & Fishman, M. C. gridlock, an HLH gene required for assembly of the aorta in zebrafish. Science 287, 1820–1824 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  34. Nye, J. S. & Kopan, R. Developmental signaling. Vertebrate ligands for Notch. Curr. Biol. 5, 966–969 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Duarte, A. et al. Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev. 18, 2474–2478 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gale, N. W. et al. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc. Natl Acad. Sci. USA 101, 15949–15954 (2004).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  37. Krebs, L. T. et al. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev. 18, 2469–2473 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fischer, A., Schumacher, N., Maier, M., Sendtner, M. & Gessler, M. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev. 18, 901–911 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. You, L. R. et al. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 435, 98–104 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

  40. Fouquet, B., Weinstein, B. M., Serluca, F. C. & Fishman, M. C. Vessel patterning in the embryo of the zebrafish: guidance by notochord. Dev. Biol. 183, 37–48 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Sumoy, L., Keasey, J. B., Dittman, T. D. & Kimelman, D. A role for notochord in axial vascular development revealed by analysis of phenotype and the expression of VEGR-2 in zebrafish flh and ntl mutant embryos. Mech. Dev. 63, 15–27 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Cleaver, O. & Krieg, P. A. VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus. Development 125, 3905–3914 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Cleaver, O. & Krieg, P. A. Notochord patterning of the endoderm. Dev. Biol. 234, 1–12 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Miquerol, L., Gertsenstein, M., Harpal, K., Rossant, J. & Nagy, A. Multiple developmental roles of VEGF suggested by a LacZ-tagged allele. Dev. Biol. 212, 307–322 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Liang, D. et al. The role of vascular endothelial growth factor (VEGF) in vasculogenesis, angiogenesis, and hematopoiesis in zebrafish development. Mech. Dev. 108, 29–43 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Vokes, S. A. et al. Hedgehog signaling is essential for endothelial tube formation during vasculogenesis. Development 131, 4371–4380 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Hogan, K. A. & Bautch, V. L. Blood vessel patterning at the embryonic midline. Curr. Top. Dev. Biol. 62, 55–85 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Reese, D. E., Hall, C. E. & Mikawa, T. Negative regulation of midline vascular development by the notochord. Dev. Cell 6, 699–708 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Nimmagadda, S. et al. BMP4 and noggin control embryonic blood vessel formation by antagonistic regulation of VEGFR-2 (Quek1) expression. Dev. Biol. 280, 100–110 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Hogan, K. A., Ambler, C. A., Chapman, D. L. & Bautch, V. L. The neural tube patterns vessels developmentally using the VEGF signaling pathway. Development 131, 1503–1513 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Nagase, T., Nagase, M., Yoshimura, K., Fujita, T. & Koshima, I. Angiogenesis within the developing mouse neural tube is dependent on sonic hedgehog signaling: possible roles of motor neurons. Genes Cells 10, 595–604 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Coffin, J. D. & Poole, T. J. Embryonic vascular development: immunohistochemical identification of the origin and subsequent morphogenesis of the major vessel primordia in quail embryos. Development 102, 735–748 (1988).

    Article  CAS  PubMed  Google Scholar 

  53. Kearney, J. B., Kappas, N. C., Ellerstrom, C., DiPaola, F. W. & Bautch, V. L. The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis. Blood 103, 4527–4535 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Krebs, L. T. et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 14, 1343–1352 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

  56. Nikolova, G. & Lammert, E. Interdependent development of blood vessels and organs. Cell Tissue Res. 314, 33–42 (2003).

    Article  PubMed  Google Scholar 

  57. Matsumoto, K., Yoshitomi, H., Rossant, J. & Zaret, K. S. Liver organogenesis promoted by endothelial cells prior to vascular function. Science 294, 559–563 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  58. LeCouter, J. et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 299, 890–893 (2003).

    Article  ADS  CAS  PubMed  Google Scholar 

  59. Lammert, E., Cleaver, O. & Melton, D. Induction of pancreatic differentiation by signals from blood vessels. Science 294, 564–567 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Lammert, E. et al. Role of VEGF-A in vascularization of pancreatic islets. Curr. Biol. 13, 1070–1074 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Yoshitomi, H. & Zaret, K. S. Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development 131, 807–817 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Field, H. A., Ober, E. A., Roeser, T. & Stainier, D. Y. Formation of the digestive system in zebrafish. I. Liver morphogenesis. Dev. Biol. 253, 279–290 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Field, H. A., Dong, P. D., Beis, D. & Stainier, D. Y. Formation of the digestive system in zebrafish. II. Pancreas morphogenesis. Dev. Biol. 261, 197–208 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Lemaigre, F. & Zaret, K. S. Liver development update: new embryo models, cell lineage control, and morphogenesis. Curr. Opin. Genet. Dev. 14, 582–590 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Eremina, V. et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J. Clin. Invest. 111, 707–716 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mattot, V. et al. Loss of the VEGF(164) and VEGF(188) isoforms impairs postnatal glomerular angiogenesis and renal arteriogenesis in mice. J. Am. Soc. Nephrol. 13, 1548–1560 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Bjarnegard, M. et al. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 131, 1847–1857 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Maynard, S. E. et al. 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 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rossant, J. & Cross, J. C. Placental development: lessons from mouse mutants. Nature Rev. Genet. 2, 538–548 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Jackson, D., Volpert, O. V., Bouck, N. & Linzer, D. I. Stimulation and inhibition of angiogenesis by placental proliferin and proliferin-related protein. Science 266, 1581–1584 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  71. Carmeliet, P. et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nature Med. 7, 575–583 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Autiero, M. et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nature Med. 9, 936–943 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Hirashima, M., Lu, Y., Byers, L. & Rossant, J. Trophoblast expression of fms-like tyrosine kinase 1 is not required for the establishment of the maternal-fetal interface in the mouse placenta. Proc. Natl Acad. Sci. USA 100, 15637–15642 (2003).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  74. Redman, C. W. & Sargent, I. L. Latest advances in understanding preeclampsia. Science 308, 1592–1594 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

  75. Levine, R. J. et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672–683 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003).

    Article  ADS  CAS  PubMed  Google Scholar 

  77. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).

    Article  ADS  CAS  PubMed  Google Scholar 

  78. Avecilla, S. T. et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nature Med. 10, 64–71 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Rafii, S. et al. Human bone marrow microvascular endothelial cells support long-term proliferation and differentiation of myeloid and megakaryocytic progenitors. Blood 86, 3353–3363 (1995).

    Article  CAS  PubMed  Google Scholar 

  80. Mohle, R., Green, D., Moore, M. A., Nachman, R. L. & Rafii, S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc. Natl Acad. Sci. USA 94, 663–668 (1997).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  81. Li, W., Johnson, S. A., Shelley, W. C. & Yoder, M. C. Hematopoietic stem cell repopulating ability can be maintained in vitro by some primary endothelial cells. Exp. Hematol. 32, 1226–1237 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Kiel, M. J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Rafii, S. & Lyden, D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nature Med. 9, 702–712 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Storkebaum, E. & Carmeliet, P. VEGF: a critical player in neurodegeneration. J. Clin. Invest. 113, 14–18 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Oosthuyse, B. et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genet. 28, 131–138 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Storkebaum, E. et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nature Neurosci. 8, 85–92 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Schwarz, Q. et al. Vascular endothelial growth factor controls neuronal migration and cooperates with Sema3A to pattern distinct compartments of the facial nerve. Genes Dev. 18, 2822–2834 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Haigh, J. J. et al. Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling. Dev. Biol. 262, 225–241 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Rosenstein, J. M. & Krum, J. M. New roles for VEGF in nervous tissue—beyond blood vessels. Exp. Neurol. 187, 246–253 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Gerber, H. P. et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nature Med. 5, 623–628 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Maes, C. et al. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech. Dev. 111, 61–73 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Zelzer, E. et al. Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 129, 1893–1904 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Maes, C. et al. Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival. J. Clin. Invest. 113, 188–199 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zelzer, E. et al. VEGFA is necessary for chondrocyte survival during bone development. Development 131, 2161–2171 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Street, J. et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc. Natl Acad. Sci. USA 99, 9656–9661 (2002).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  96. Nakagawa, M. et al. Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS Lett. 473, 161–164 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Gerber, H. P. et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 417, 954–958 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  98. Arsic, N. et al. Vascular endothelial growth factor stimulates skeletal muscle regeneration in vivo. Mol. Ther. 10, 844–854 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Compernolle, V. et al. Loss of HIF-2± and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nature Med. 8, 702–710 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Sharpe, J. et al. Optical projection tomography as a tool for 3D microscopy and gene expression studies. Science 296, 541–545 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank S. Quaggin (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada) for unpublished results, J. Walls (Mouse Imaging Centre, Hospital for Sick Children, Toronto, Canada) for assistance with preparation of Fig. 1, and M. Hirashima (Keio University, Tokyo, Japan) and members of the Rossant laboratory for helpful discussions. J.R. is a distinguished investigator of the Canadian Institutes of Health Research. L.C. is a postdoctoral fellow of the Canadian Institutes of Health Research and K.C. is a C. J. Martin Fellow of the Australian National Health and Medical Council.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Janet Rossant.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Author Information Reprints and pemissions information is available at npg.nature.com/reprintsandpermissions.

Supplementary information

Supplementary Table 1

Mutations of genes involved in vasculo–angiogenesis (DOC 225 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Coultas, L., Chawengsaksophak, K. & Rossant, J. Endothelial cells and VEGF in vascular development. Nature 438, 937–945 (2005). https://doi.org/10.1038/nature04479

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04479

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing