Blood vessels and nerves: common signals, pathways and diseases

Key Points

  • This article presents an overview of the emerging evidence of how neurons and blood vessels share common genetic pathways to acquire their fate, grow, pattern and navigate, and how both the vascular and neural systems are linked.

  • Both neural and vascular progenitors use common genetic pathways to differentiate into specialized cell subtypes, all of which are optimally equipped to perform specific functions.

  • Angiogenesis and neurogenesis (for example, the birth of new neural stem cells) are closely linked and influence one another — this review highlights the molecular signals that are involved.

  • The organization of both the vascular and nervous systems requires mechanisms that determine boundary formation and the segregation of distinct cell populations: both the vascular and neural systems use common signals.

  • Wiring of the nervous and vascular networks involves the sophisticated use of attractant and repellant signals. Remarkably, both systems often use common genetic pathways to achieve this goal.

  • Vessels and nerves often track together — the recent genetic insights into how they do so are reviewed.

  • There are many more neuro-vascular disorders than originally anticipated; a perspective on their genetic basis and possible treatment is discussed.

Abstract

Both blood vessels and nerves are vital channels to and from tissues. Recent genetic insights show that they have much more in common than was originally anticipated. They use similar signals and principles to differentiate, grow and navigate towards their targets. Moreover, the vascular and nervous systems cross-talk and, when dysregulated, this contributes to medically important diseases. The realization that both systems use common genetic pathways should not only form links between vascular biology and neuroscience, but also promises to accelerate the discovery of new mechanistic insights and therapeutic opportunities.

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Figure 1: Neural and vascular cell fate.
Figure 2: Neural stem cells at the vascular niche.
Figure 3: Role of ephrin/Eph interactions in neural crest migration and intersegmental-vessel branching.
Figure 4: A balance of Sema3A and VEGF determines Nrp1 mediated growth-cone guidance.
Figure 5: Role of matrix association of VEGF in vessel branching.
Figure 6: Coordinated patterning of nerves with blood vessels.
Figure 7: Role of VEGF in motor neuron degeneration.

References

  1. 1

    Temple, S. The development of neural stem cells. Nature 414, 112–117 (2001). An overview of the molecular and cellular mechanisms of neural stem cells.

    CAS  Article  Google Scholar 

  2. 2

    Panchision, D. M. & McKay, R. D. The control of neural stem cells by morphogenic signals. Curr. Opin. Genet. Dev. 12, 478–487 (2002).

    CAS  PubMed  Google Scholar 

  3. 3

    Osterfield, M., Kirschner, M. W. & Flanagan, J. G. Graded positional information. Interpretation for both fate and guidance. Cell 113, 425–428 (2003). A recent overview that highlights how morphogens control neural development.

    CAS  PubMed  Google Scholar 

  4. 4

    Hitoshi, S. et al. Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev. 16, 846–858 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Gaiano, N. & Fishell, G. The role of notch in promoting glial and neural stem cell fates. Annu. Rev. Neurosci. 25, 471–490 (2002).

    CAS  PubMed  Google Scholar 

  6. 6

    Patten, I. & Placzek, M. The role of Sonic hedgehog in neural tube patterning. Cell Mol. Life Sci. 57, 1695–1708 (2000).

    CAS  PubMed  Google Scholar 

  7. 7

    Rowitch, D. H., Lu, Q. R., Kessaris, N. & Richardson, W. D. An 'oligarchy' rules neural development. Trends Neurosci. 25, 417–422 (2002).

    CAS  PubMed  Google Scholar 

  8. 8

    Mehler, M. F. Mechanisms regulating lineage diversity during mammalian cerebral cortical neurogenesis and gliogenesis. Results Probl. Cell Differ. 39, 27–52 (2002).

    CAS  PubMed  Google Scholar 

  9. 9

    Lyden, D. et al. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401, 670–677 (1999). This paper documents how bHLH-repressors affect both neurogenesis and angiogenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Wang, S., Sdrulla, A., Johnson, J. E., Yokota, Y. & Barres, B. A. A role for the helix–loop–helix protein Id2 in the control of oligodendrocyte development. Neuron 29, 603–614 (2001).

    CAS  Google Scholar 

  11. 11

    Dupin, E., Real, C. & Ledouarin, N. The neural crest stem cells: control of neural crest cell fate and plasticity by endothelin-3. An. Acad. Bras. Cienc. 73, 533–545 (2001).

    CAS  PubMed  Google Scholar 

  12. 12

    Knecht, A. K. & Bronner-Fraser, M. Induction of the neural crest: a multigene process. Nature Rev. Genet. 3, 453–461 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Etchevers, H. C., Couly, G. & Le Douarin, N. M. Morphogenesis of the branchial vascular sector. Trends Cardiovasc. Med. 12, 299–304 (2002). A recent overview that illustrates the role of neural crest cells in vascular development.

    PubMed  Google Scholar 

  14. 14

    Aybar, M. J. & Mayor, R. Early induction of neural crest cells: lessons learned from frog, fish and chick. Curr. Opin. Genet. Dev. 12, 452–458 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Soriano, P. The PDGFα receptor is required for neural crest cell development and for normal patterning of the somites. Development 124, 2691–2700 (1997).

    CAS  PubMed  Google Scholar 

  16. 16

    Maschhoff, K. L. & Baldwin, H. S. Molecular determinants of neural crest migration. Am. J. Med. Genet. 97, 280–288 (2000). Overview of the genetics of neural crest cell migration.

    CAS  PubMed  Google Scholar 

  17. 17

    Kawasaki, T. et al. A requirement for neuropilin-1 in embryonic vessel formation. Development 126, 4895–4902 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Feiner, L. et al. Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development 128, 3061–3070 (2001).

    CAS  PubMed  Google Scholar 

  19. 19

    Kurihara, Y. et al. Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1. J. Clin. Invest. 96, 293–300 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Williams, D. E. et al. Identification of a ligand for the c-kit proto-oncogene. Cell 63, 167–174 (1990).

    CAS  PubMed  Google Scholar 

  21. 21

    Shah, N. M., Groves, A. K. & Anderson, D. J. Alternative neural crest cell fates are instructively promoted by TGFβ superfamily members. Cell 85, 331–343 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Carmeliet, P. One cell, two fates. Nature 408, 43,45 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Mikkola, H. K. & Orkin, S. H. The search for the hemangioblast. J. Hematother. Stem Cell Res. 11, 9–17 (2002).

    PubMed  PubMed Central  Google Scholar 

  24. 24

    Carmeliet, P. Angiogenesis in health and disease. Nature Med. 9, 653–660 (2003). A recent overview of the molecular and cellular mechanisms of vessel growth in health and disease.

    CAS  PubMed  Google Scholar 

  25. 25

    Cleaver, O. & Melton, D. A. Endothelial signaling during development. Nature Med. 9, 661–668 (2003).

    CAS  PubMed  Google Scholar 

  26. 26

    Rovainen, C. M. Labeling of developing vascular endothelium after injections of rhodamine-dextran into blastomeres of Xenopus laevis. J. Exp. Zool. 259, 209–221 (1991).

    CAS  PubMed  Google Scholar 

  27. 27

    Childs, S., Chen, J. N., Garrity, D. M. & Fishman, M. C. Patterning of angiogenesis in the zebrafish embryo. Development 129, 973–982 (2002).

    CAS  PubMed  Google Scholar 

  28. 28

    Liao, W., Ho, C. Y., Yan, Y. L., Postlethwait, J. & Stainier, D. Y. Hhex and scl function in parallel to regulate early endothelial and blood differentiation in zebrafish. Development 127, 4303–4313 (2000).

    CAS  Google Scholar 

  29. 29

    Brown, L. A. et al. Insights into early vasculogenesis revealed by expression of the ETS-domain transcription factor Fli-1 in wild-type and mutant zebrafish embryos. Mech. Dev. 90, 237–252 (2000).

    CAS  Google Scholar 

  30. 30

    Carmeliet, P. Controlling the cellular brakes. Nature 401, 657–658 (1999).

    CAS  PubMed  Google Scholar 

  31. 31

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

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Abbot, N. J. Glial–endothelial communication in physiology and pathology. J. Neurochem. 85 (Suppl.) 2 (2003).

    Google Scholar 

  33. 33

    LeCouter, J., Lin, R. & Ferrara, N. Endocrine gland-derived VEGF and the emerging hypothesis of organ-specific regulation of angiogenesis. Nature Med. 8, 913–917 (2002).

    CAS  Google Scholar 

  34. 34

    Ruoslahti, E. Specialization of tumour vasculature. Nature Rev. Cancer 2, 83–90 (2002).

    Google Scholar 

  35. 35

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

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    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).

    CAS  PubMed  Google Scholar 

  37. 37

    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).

    CAS  PubMed  Google Scholar 

  38. 38

    Hall, C. J., Flores, M. V., Davidson, A. J., Crosier, K. E. & Crosier, P. S. Radar is required for the establishment of vascular integrity in the zebrafish. Dev. Biol. 251, 105–117 (2002).

    CAS  PubMed  Google Scholar 

  39. 39

    Damert, A., Miquerol, L., Gertsenstein, M., Risau, W. & Nagy, A. Insufficient VEGFA activity in yolk sac endoderm compromises haematopoietic and endothelial differentiation. Development 129, 1881–1892 (2002).

    CAS  PubMed  Google Scholar 

  40. 40

    Ferrara, N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin. Oncol. 29, 10–14 (2002).

    CAS  PubMed  Google Scholar 

  41. 41

    Baron, M. Induction of embryonic hematopoietic and endothelial stem/progenitor cells by hedgehog-mediated signals. Differentiation 68, 175–185 (2001).

    CAS  PubMed  Google Scholar 

  42. 42

    Dyer, M. A., Farrington, S. M., Mohn, D., Munday, J. R. & Baron, M. H. Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development 128, 1717–1730 (2001).

    CAS  Google Scholar 

  43. 43

    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).

    CAS  PubMed  Google Scholar 

  44. 44

    Othman-Hassan, K. et al. Arterial identity of endothelial cells is controlled by local cues. Dev. Biol. 237, 398–409 (2001).

    CAS  PubMed  Google Scholar 

  45. 45

    Lawson, N. D., Vogel, A. M. & Weinstein, B. M. Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev. Cell 3, 127–136 (2002). This paper explains the genetic pathways that determine arterial endothelial cell fate.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Lawson, N. D. & Weinstein, B. M. Arteries and veins: making a difference with zebrafish. Nature Rev. Genet. 3, 674–682 (2002).

    CAS  PubMed  Google Scholar 

  47. 47

    Chen, J. N. et al. Mutations affecting the cardiovascular system and other internal organs in zebrafish. Development 123, 293–302 (1996).

    CAS  PubMed  Google Scholar 

  48. 48

    Mukouyama, Y. S., Shin, D., Britsch, S., Taniguchi, M. & Anderson, D. J. Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin. Cell 109, 693–705 (2002). This study provides genetic insights into how arteries are guided by nerves.

    CAS  Google Scholar 

  49. 49

    Stalmans, I. et al. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J. Clin. Invest. 109, 327–336 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Visconti, R. P., Richardson, C. D. & Sato, T. N. Orchestration of angiogenesis and arteriovenous contribution by angiopoietins and vascular endothelial growth factor (VEGF). Proc. Natl Acad. Sci. USA 99, 8219–8224 (2002).

    CAS  PubMed  Google Scholar 

  51. 51

    Itoh, M. et al. Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev. Cell 4, 67–82 (2003).

    CAS  PubMed  Google Scholar 

  52. 52

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

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    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). This paper reports how bHLH proteins determine arterial cell fate.

    CAS  Google Scholar 

  54. 54

    Lawson, N. D., Mugford, J. W., Diamond, B. A. & Weinstein, B. M. Phospholipase C γ-1 is required downstream of vascular endothelial growth factor during arterial development. Genes Dev. 17, 1346–1351 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Kalimo, H., Ruchoux, M. M., Viitanen, M. & Kalaria, R. N. CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol. 12, 371–384 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Iso, T., Hamamori, Y. & Kedes, L. Notch signaling in vascular development. Arterioscler. Thromb. Vasc. Biol. 23, 543–553 (2003).

    CAS  PubMed  Google Scholar 

  57. 57

    Taylor, K. L., Henderson, A. M. & Hughes, C. C. Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. Microvasc. Res. 64, 372–383 (2002).

    CAS  PubMed  Google Scholar 

  58. 58

    Compernolle, V. et al. Loss of HIF-2α 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).

    CAS  PubMed  Google Scholar 

  59. 59

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

    CAS  Google Scholar 

  60. 60

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

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

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Bahary, N. & Zon, L. I. Endothelium — chicken soup for the endoderm. Science 294, 530–531 (2001).

    CAS  PubMed  Google Scholar 

  63. 63

    Stainier, D. Y. et al. Mutations affecting the formation and function of the cardiovascular system in the zebrafish embryo. Development 123, 285–292 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Zerlin, M. & Goldman, J. E. Interactions between glial progenitors and blood vessels during early postnatal corticogenesis: blood vessel contact represents an early stage of astrocyte differentiation. J. Comp. Neurol. 387, 537–546 (1997).

    CAS  PubMed  Google Scholar 

  65. 65

    Huxlin, K. R., Sefton, A. J. & Furby, J. H. The origin and development of retinal astrocytes in the mouse. J. Neurocytol. 21, 530–544 (1992).

    CAS  PubMed  Google Scholar 

  66. 66

    Louissaint, A., Rao, S., Leventhal, C. & Goldman, S. A. Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 34, 945–960 (2002). This report documents how VEGF-driven angiogenesis stimulates BDNF-driven neurogenesis.

    CAS  Google Scholar 

  67. 67

    Palmer, T. D., Willhoite, A. R. & Gage, F. H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000). This study highlights the link between angiogenesis and neurogenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Mi, H., Haeberle, H. & Barres, B. A. Induction of astrocyte differentiation by endothelial cells. J. Neurosci. 21, 1538–1547 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Yang, K. & Cepko, C. L. Flk-1, a receptor for vascular endothelial growth factor (VEGF) is expressed by retinal progenitor cells. J. Neurosci. 16, 6089–6099 (1996).

    CAS  Google Scholar 

  70. 70

    Yourey, P. A., Gohari, S., Su, J. L. & Alderson, R. F. Vascular endothelial cell growth factors promote the in vitro development of rat photoreceptor cells. J. Neurosci. 20, 6781–6788 (2000).

    CAS  Google Scholar 

  71. 71

    Jin, K. et al. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Natl Acad. Sci. USA 99, 11946–11950 (2002). This study documents how the prototype angiogenic factor VEGF affects neurogenesis.

    CAS  PubMed  Google Scholar 

  72. 72

    Zhu, Y., Jin, K., Mao, X. O. & Greenberg, D. A. Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. FASEB J. 17, 186–193 (2003).

    CAS  PubMed  Google Scholar 

  73. 73

    Bagnard, D. et al. Semaphorin 3A-vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor. J. Neurosci. 21, 3332–3341 (2001).

    CAS  PubMed  Google Scholar 

  74. 74

    Miao, H. Q. et al. Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: functional competition of collapsin-1 and vascular endothelial growth factor-165. J. Cell Biol. 146, 233–242 (1999). This paper illustrates how the neurorepellent Sema3A and VEGF antagonistically affect endothelial cells through binding neuropilin-1.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Leventhal, C., Rafii, S., Rafii, D., Shahar, A. & Goldman, S. A. Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol. Cell Neurosci. 13, 450–464 (1999).

    CAS  PubMed  Google Scholar 

  76. 76

    Black, J. E., Isaacs, K. R., Anderson, B. J., Alcantara, A. A. & Greenough, W. T. Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc. Natl Acad. Sci. USA 87, 5568–5572 (1990).

    CAS  Google Scholar 

  77. 77

    Kokaia, Z. & Lindvall, O. Neurogenesis after ischaemic brain insults. Curr. Opin Neurobiol. 13, 127–132 (2003).

    CAS  PubMed  Google Scholar 

  78. 78

    Monje, M. L., Mizumatsu, S., Fike, J. R. & Palmer, T. D. Irradiation induces neural precursor-cell dysfunction. Nature Med. 8, 955–962 (2002).

    CAS  PubMed  Google Scholar 

  79. 79

    Cooke, J. E. & Moens, C. B. Boundary formation in the hindbrain: Eph only it were simple. Trends Neurosci. 25, 260–267 (2002). A review of the role of ephrins in boundary formation in the brain.

    CAS  PubMed  Google Scholar 

  80. 80

    Tepass, U., Godt, D. & Winklbauer, R. Cell sorting in animal development: signalling and adhesive mechanisms in the formation of tissue boundaries. Curr. Opin. Genet. Dev. 12, 572–582 (2002).

    CAS  Google Scholar 

  81. 81

    Krull, C. E. Segmental organization of neural crest migration. Mech. Dev. 105, 37–45 (2001).

    CAS  Google Scholar 

  82. 82

    Mellitzer, G., Xu, Q. & Wilkinson, D. G. Eph receptors and ephrins restrict cell intermingling and communication. Nature 400, 77–81 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Coulthard, M. G. et al. The role of the Eph–ephrin signalling system in the regulation of developmental patterning. Int. J. Dev. Biol. 46, 375–384 (2002).

    CAS  PubMed  Google Scholar 

  84. 84

    Cooke, J. et al. Eph signalling functions downstream of Val to regulate cell sorting and boundary formation in the caudal hindbrain. Development 128, 571–580 (2001).

    CAS  PubMed  Google Scholar 

  85. 85

    Xu, Q., Alldus, G., Holder, N. & Wilkinson, D. G. Expression of truncated Sek-1 receptor tyrosine kinase disrupts the segmental restriction of gene expression in the Xenopus and zebrafish hindbrain. Development 121, 4005–4016 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Holmberg, J. & Frisen, J. Ephrins are not only unattractive. Trends Neurosci. 25, 239–243 (2002).

    CAS  PubMed  Google Scholar 

  87. 87

    Adams, R. H. & Klein, R. Eph receptors and ephrin ligands: essential mediators of vascular development. Trends Cardiovasc. Med. 10, 183–188 (2000). An overview of the role of ephrins in vascular development.

    CAS  PubMed  Google Scholar 

  88. 88

    Cheng, N., Brantley, D. M. & Chen, J. The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev. 13, 75–85 (2002).

    CAS  PubMed  Google Scholar 

  89. 89

    Gale, N. W. et al. Ephrin-B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth-muscle cells. Dev. Biol. 230, 151–160 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Shin, D. et al. Expression of ephrinB2 identifies a stable genetic difference between arterial and venous vascular smooth muscle as well as endothelial cells, and marks subsets of microvessels at sites of adult neovascularization. Dev. Biol. 230, 139–150 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    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). A seminal study that documents the role of ephrins in vascular development.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Hirano, S., Suzuki, S. T. & Redies, C. M. The cadherin superfamily in neural development: diversity, function and interaction with other molecules. Front. Biosci. 8, 306–355 (2003).

    Google Scholar 

  94. 94

    Dejana, E., Spagnuolo, R. & Bazzoni, G. Interendothelial junctions and their role in the control of angiogenesis, vascular permeability and leukocyte transmigration. Thromb. Haemost. 86, 308–315 (2001).

    CAS  PubMed  Google Scholar 

  95. 95

    Inoue, T. et al. Role of cadherins in maintaining the compartment boundary between the cortex and striatum during development. Development 128, 561–569 (2001).

    CAS  PubMed  Google Scholar 

  96. 96

    Guthrie, S. Neuronal development: sorting out motor neurons. Curr. Biol. 12, 488–490 (2002). This overview highlights how cadherins are involved in sorting neurons.

    Google Scholar 

  97. 97

    Carmeliet, P. et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98, 147–157 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Wolburg, H. & Lippoldt, A. Tight junctions of the blood–brain barrier: development, composition and regulation. Vascul. Pharmacol. 38, 323–337 (2002).

    CAS  PubMed  Google Scholar 

  99. 99

    Gerhardt, H., Wolburg, H. & Redies, C. N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev. Dyn. 218, 472–479 (2000).

    CAS  PubMed  Google Scholar 

  100. 100

    Lawson, N. D. & Weinstein, B. M. In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev. Biol. 248, 307–318 (2002).

    CAS  Google Scholar 

  101. 101

    Gerhardt, H. et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J. Cell. Biol. 161, 1163–1177 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Dickson, B. J. Molecular mechanisms of axon guidance. Science 298, 1959–1964 (2002). A recent overview of the cellular and molecular mechanisms of axon guidance.

    CAS  Google Scholar 

  103. 103

    Yamamoto, N., Tamada, A. & Murakami, F. Wiring of the brain by a range of guidance cues. Prog. Neurobiol. 68, 393–407 (2002).

    PubMed  Google Scholar 

  104. 104

    Cooper, H. M. Axon guidance receptors direct growth cone pathfinding: rivalry at the leading edge. Int. J. Dev. Biol. 46, 621–631 (2002).

    CAS  PubMed  Google Scholar 

  105. 105

    McFarlane, S. Attraction vs. repulsion: the growth cone decides. Biochem. Cell Biol. 78, 563–568 (2000).

    CAS  PubMed  Google Scholar 

  106. 106

    Nguyen-Ba-Charvet, K. T. & Chedotal, A. Role of Slit proteins in the vertebrate brain. J. Physiol. Paris 96, 91–98 (2002).

    CAS  PubMed  Google Scholar 

  107. 107

    Guthrie, S. Axon guidance: Robos make the rules. Curr. Biol. 11, 300–303 (2001). A review of the genetic pathways, in particular of the Robo receptors, which determine neuronal route finding.

    Google Scholar 

  108. 108

    Wong, K., Park, H. T., Wu, J. Y. & Rao, Y. Slit proteins: molecular guidance cues for cells ranging from neurons to leukocytes. Curr. Opin. Genet. Dev. 12, 583–591 (2002).

    CAS  PubMed  Google Scholar 

  109. 109

    Kidd, T., Bland, K. S. & Goodman, C. S. Slit is the midline repellent for the robo receptor in Drosophila. Cell 96, 785–794 (1999).

    CAS  Google Scholar 

  110. 110

    Fricke, C., Lee, J. S., Geiger-Rudolph, S., Bonhoeffer, F. & Chien, C. B. astray, a zebrafish roundabout homolog required for retinal axon guidance. Science 292, 507–510 (2001).

    CAS  Google Scholar 

  111. 111

    Plump, A. S. et al. Slit1 and Slit2 cooperate to prevent premature midline crossing of retinal axons in the mouse visual system. Neuron 33, 219–232 (2002).

    CAS  PubMed  Google Scholar 

  112. 112

    Manitt, C. & Kennedy, T. E. Where the rubber meets the road: netrin expression and function in developing and adult nervous systems. Prog. Brain Res. 137, 425–442 (2002).

    CAS  PubMed  Google Scholar 

  113. 113

    Giger, R. J. & Kolodkin, A. L. Silencing the siren: guidance cue hierarchies at the CNS midline. Cell 105, 1–4 (2001).

    CAS  PubMed  Google Scholar 

  114. 114

    Knoll, B. & Drescher, U. Ephrin-As as receptors in topographic projections. Trends Neurosci. 25, 145–149 (2002).

    CAS  Google Scholar 

  115. 115

    Feldheim, D. A. et al. Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 25, 563–574 (2000).

    CAS  Google Scholar 

  116. 116

    McLaughlin, T., Hindges, R. & O'Leary, D. D. Regulation of axial patterning of the retina and its topographic mapping in the brain. Curr. Opin. Neurobiol. 13, 57–69 (2003).

    CAS  PubMed  Google Scholar 

  117. 117

    Murai, K. K., Nguyen, L. N., Irie, F., Yamaguchi, Y. & Pasquale, E. B. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nature Neurosci. 6, 153–160 (2003).

    CAS  PubMed  Google Scholar 

  118. 118

    Adams, R. H. et al. The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration. Cell 104, 57–69 (2001).

    CAS  PubMed  Google Scholar 

  119. 119

    Bagri, A. & Tessier-Lavigne, M. Neuropilins as semaphorin receptors: in vivo functions in neuronal cell migration and axon guidance. Adv. Exp. Med. Biol. 515, 13–31 (2002). An overview of the role of semaphorins and their neuropilin receptors in neurobiology.

    CAS  PubMed  Google Scholar 

  120. 120

    Pasterkamp, R. J. & Kolodkin, A. L. Semaphorin junction: making tracks toward neural connectivity. Curr. Opin. Neurobiol. 13, 79–89 (2003).

    CAS  PubMed  Google Scholar 

  121. 121

    Puschel, A. W. The function of neuropilin/plexin complexes. Adv. Exp. Med. Biol. 515, 71–80 (2002).

    PubMed  Google Scholar 

  122. 122

    Song, H. et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 281, 1515–1518 (1998).

    CAS  Google Scholar 

  123. 123

    Neufeld, G. et al. The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc. Med. 12, 13–19 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Isogai, S., Horiguchi, M. & Weinstein, B. M. The vascular anatomy of the developing zebrafish: an atlas of embryonic and early larval development. Dev. Biol. 230, 278–301 (2001).

    CAS  PubMed  Google Scholar 

  125. 125

    Pugh, C. W. & Ratcliffe, P. J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nature Med. 9, 677–684 (2003).

    CAS  Google Scholar 

  126. 126

    Carmeliet, P. et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nature Med. 5, 495–502 (1999).

    CAS  PubMed  Google Scholar 

  127. 127

    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).

    CAS  PubMed  Google Scholar 

  128. 128

    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). A study that reports a neurotrophic and vascular role for the prototype angiogenic factor VEGF in motor neuron degeneration.

    CAS  Google Scholar 

  129. 129

    Gerber, H. P. et al. VEGF is required for growth and survival in neonatal mice. Development 126, 1149–1159 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Egginton, S., Zhou, A. L., Brown, M. D. & Hudlicka, O. Unorthodox angiogenesis in skeletal muscle. Cardiovasc. Res. 49, 634–646 (2001).

    CAS  PubMed  Google Scholar 

  131. 131

    Djonov, V. G., Kurz, H. & Burri, P. H. Optimality in the developing vascular system: branching remodeling by means of intussusception as an efficient adaptation mechanism. Dev. Dyn. 224, 391–402 (2002).

    PubMed  Google Scholar 

  132. 132

    Helbling, P. M., Saulnier, D. M. & Brandli, A. W. The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis. Development 127, 269–278 (2000).

    CAS  Google Scholar 

  133. 133

    Gerety, S. S. & Anderson, D. J. Cardiovascular ephrinB2 function is essential for embryonic angiogenesis. Development 129, 1397–1410 (2002).

    CAS  PubMed  Google Scholar 

  134. 134

    Ruhrberg, C. et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 16, 2684–2698 (2002). A genetic study that documents the role of VEGF isoforms in vessel patterning and branching.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    van der Zwaag, B. et al. PLEXIN-D1, a novel plexin family member, is expressed in vascular endothelium and the central nervous system during mouse embryogenesis. Dev. Dyn. 225, 336–343 (2002).

    CAS  PubMed  Google Scholar 

  136. 136

    Shoji, W., Isogai, S., Sato-Maeda, M., Obinata, M. & Kuwada, J. Y. Semaphorin3a1 regulates angioblast migration and vascular development in zebrafish embryos. Development 130, 3227–3236 (2003).

    CAS  PubMed  Google Scholar 

  137. 137

    Huminiecki, L., Gorn, M., Suchting, S., Poulsom, R. & Bicknell, R. Magic roundabout is a new member of the roundabout receptor family that is endothelial specific and expressed at sites of active angiogenesis. Genomics 79, 547–552 (2002).

    CAS  PubMed  Google Scholar 

  138. 138

    Stalmans, I. et al. VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nature Med. 9, 173–182 (2003). A study that uses genetics in mice, zebrafish and humans to document a role of VEGF-isoforms in the patterning of the great thoracic arteries.

    CAS  PubMed  Google Scholar 

  139. 139

    Carmeliet, P. Fibroblast growth factor-1 stimulates branching and survival of myocardial arteries: a goal for therapeutic angiogenesis? Circ. Res. 87, 176–178 (2000).

    CAS  PubMed  Google Scholar 

  140. 140

    Hilgers, K. F., Norwood, V. F. & Gomez, R. A. Angiotensin's role in renal development. Semin. Nephrol. 17, 492–501 (1997).

    CAS  PubMed  Google Scholar 

  141. 141

    Lee, S. H., Schloss, D. J., Jarvis, L., Krasnow, M. A. & Swain, J. L. Inhibition of angiogenesis by a mouse sprouty protein. J. Biol. Chem. 276, 4128–4133 (2001).

    CAS  PubMed  Google Scholar 

  142. 142

    Honma, Y. et al. Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron 35, 267–282 (2002). This study provides genetic evidence for how vessel-produced artemin directs nerve patterning.

    CAS  Google Scholar 

  143. 143

    Bates, D. et al. Neurovascular congruence results from a shared patterning mechanism that utilizes semaphorin3A and neuropilin-1. Dev. Biol. 255, 77–98 (2003).

    CAS  PubMed  Google Scholar 

  144. 144

    Borisov, A. B., Huang, S. K. & Carlson, B. M. Remodeling of the vascular bed and progressive loss of capillaries in denervated skeletal muscle. Anat. Rec. 258, 292–304 (2000).

    CAS  PubMed  Google Scholar 

  145. 145

    Zukowska, Z., Grant, D. S. & Lee, E. W. Neuropeptide Y: a novel mechanism for ischemic angiogenesis. Trends Cardiovasc. Med. 13, 86–92 (2003).

    CAS  PubMed  Google Scholar 

  146. 146

    Teunis, M. A. et al. Reduced tumor growth, experimental metastasis formation, and angiogenesis in rats with a hyperreactive dopaminergic system. FASEB J. 16, 1465–1467 (2002).

    CAS  PubMed  Google Scholar 

  147. 147

    Basu, S. et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nature Med. 7, 569–574 (2001).

    CAS  PubMed  Google Scholar 

  148. 148

    Heeschen, C. et al. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nature Med. 7, 833–839 (2001).

    CAS  PubMed  Google Scholar 

  149. 149

    Donovan, M. J. et al. Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization. Development 127, 4531–4540 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Calza, L., Giardino, L., Giuliani, A., Aloe, L. & Levi-Montalcini, R. Nerve growth factor control of neuronal expression of angiogenetic and vasoactive factors. Proc. Natl Acad. Sci. USA 98, 4160–4165 (2001).

    CAS  PubMed  Google Scholar 

  151. 151

    Carmichael, S. T. Plasticity of cortical projections after stroke. Neuroscientist 9, 64–75 (2003).

    PubMed  Google Scholar 

  152. 152

    Carmeliet, P. Creating unique blood vessels. Nature 412, 868–869 (2001).

    CAS  PubMed  Google Scholar 

  153. 153

    Cleveland, D. W. & Rothstein, J. D. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nature Rev. Neurosci. 2, 806–819 (2001).

    CAS  Google Scholar 

  154. 154

    Lambrechts, D. et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nature Genet. 34, 383–394 (2003).

    CAS  PubMed  Google Scholar 

  155. 155

    Poltorak, Z., Cohen, T. & Neufeld, G. The VEGF splice variants: properties, receptors, and usage for the treatment of ischemic diseases. Herz 25, 126–129 (2000).

    CAS  PubMed  Google Scholar 

  156. 156

    Kalaria, R. N. Small vessel disease and Alzheimer's dementia: pathological considerations. Cerebrovasc. Disc. 13 (Suppl.), 48–52 (2002). An overview that highlights the role of blood vessels in neurodegenerative Alzheimer Disease.

    CAS  Google Scholar 

  157. 157

    Wick, A. et al. Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J. Neurosci. 22, 6401–6407 (2002).

    CAS  PubMed  Google Scholar 

  158. 158

    Isner, J. M., Ropper, A. & Hirst, K. VEGF gene transfer for diabetic neuropathy. Hum. Gene Ther. 12, 1593–1594 (2001).

    CAS  PubMed  Google Scholar 

  159. 159

    Schratzberger, P. et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J. Clin. Invest. 107, 1083–1092 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Sondell, M., Sundler, F. & Kanje, M. Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur. J. Neurosci. 12, 4243–4254 (2000).

    CAS  PubMed  Google Scholar 

  161. 161

    Hobson, M. I., Green, C. J. & Terenghi, G. VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy. J. Anat. 197, 591–605 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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Glossary

NEUROECTODERM

The embryonic ectoderm that develops into the central and peripheral nervous systems.

NEURON

A nerve cell that contains a cell body from which dendrites and axons extend to adjacent neurons, and receive and transmit electrical and chemical signals, respectively.

GLIAL CELL

A non-neuronal cell in the brain that lacks axons and dendrites. These cells are subdivided into astrocytes (which make contact with neurons and blood vessels), oligodendrocytes and Schwann cells (which form myelin around axons in the central and peripheral nervous system, respectively), ependymal cells (which line the ventricles) and others.

LATERAL INHIBITION

The process by which a neuron that expresses Notch transmits inhibitory signals to adjacent precursors.

MORPHOGEN

A substance that specifies cell identity as a function of its concentration.

MOTOR NEURON

A nerve cell that innervates muscle cells.

EPENDYMAL CELLS

The cells that line the passageways in the brain, where the special fluid that protects the brain and spinal cord (cerebrospinal fluid) is made and stored.

OLIGODENDROCYTE

A type of non-neuronal brain cell that lacks axons and dendrites, which forms axons in the central nervous system.

MESECTODERM

Mesenchymal cells that are derived from the neural crest.

MESODERM

One of the three germ layers of the early embryo, which consists of the notochord, muscle and blood.

EPICARDIAL CELLS

The cells that line the outside of the heart.

ANGIOBLASTS

Endothelial progenitors that give rise to endothelial cells.

HAEMANGIOBLASTS

The common ancestor of haematopoietic and endothelial cells.

INTERSEGMENTAL VESSELS

Vessels that carry blood from the dorsal aorta between somites to the sides of the neural tube.

MORPHOLINO KNOCKDOWN

The process by which morpholino DNA oligomers lower gene expression by inhibiting translation.

SCHWANN CELL

A type of non-neuronal brain cell that lacks axons and dendrites, which forms axons in the peripheral nervous system.

HYPOMORPH MUTATION

A mutation that does not completely eliminate the wild-type function of a gene and therefore causes a less severe phenotype than a loss-of-function (or null) mutation.

ASTROGLIAL CELL

(Astrocyte). A star-shaped glial cell that supports the tissues of the central nervous system.

NEURITE

Any neuronal process (axon or dendrite). This term is typically used to refer to the processes of neurons in cell culture.

RHOMBOMERES

Segments of the embryonic hindbrain, which is also known as the rhombencephalon.

TELENCEPHALON

The anterior portion of the forebrain, which is also known as the cerebrum, the outer layer of which contains the cortex.

IPSILATERAL

The same side.

COMMISSURAL AXONS

The commissures are fibre tracts that connect the two brain hemispheres.

TECTUM

The dorsal part, or roof, of the midbrain.

FASCICULATION

The aggregation of neuronal processes to form a bundle.

ANGIOGENIC SPROUTING

The formation of new blood-vessel branches.

HAEMODYNAMICS

Concerned with the forces that are generated by the heart, and the motion of blood through the cardiovascular system.

ISCHAEMIA

A lack of blood supply to an area of the body.

HYPOPERFUSED

A diminished blood supply to the tissues.

ARBORIZATION

Branching out.

HAEMANGIOMA

A purple-red mark on the skin that is caused by an excess of blood vessels.

METAMERE

A division or segment of the body.

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Carmeliet, P. Blood vessels and nerves: common signals, pathways and diseases. Nat Rev Genet 4, 710–720 (2003). https://doi.org/10.1038/nrg1158

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