Review Article | Published:

Blood vessels and nerves: common signals, pathways and diseases

Nature Reviews Genetics volume 4, pages 710720 (2003) | Download Citation

Subjects

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.

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 4.

    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).

  5. 5.

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

  6. 6.

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

  7. 7.

    , , & An 'oligarchy' rules neural development. Trends Neurosci. 25, 417–422 (2002).

  8. 8.

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

  9. 9.

    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.

  10. 10.

    , , , & A role for the helix–loop–helix protein Id2 in the control of oligodendrocyte development. Neuron 29, 603–614 (2001).

  11. 11.

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

  12. 12.

    & Induction of the neural crest: a multigene process. Nature Rev. Genet. 3, 453–461 (2002).

  13. 13.

    , & 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.

  14. 14.

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

  15. 15.

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

  16. 16.

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

  17. 17.

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

  18. 18.

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

  19. 19.

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

  20. 20.

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

  21. 21.

    , & Alternative neural crest cell fates are instructively promoted by TGFβ superfamily members. Cell 85, 331–343 (1996).

  22. 22.

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

  23. 23.

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

  24. 24.

    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.

  25. 25.

    & Endothelial signaling during development. Nature Med. 9, 661–668 (2003).

  26. 26.

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

  27. 27.

    , , & Patterning of angiogenesis in the zebrafish embryo. Development 129, 973–982 (2002).

  28. 28.

    , , , & Hhex and scl function in parallel to regulate early endothelial and blood differentiation in zebrafish. Development 127, 4303–4313 (2000).

  29. 29.

    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).

  30. 30.

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

  31. 31.

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

  32. 32.

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

  33. 33.

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

  34. 34.

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

  35. 35.

    , , & Gridlock signalling pathway fashions the first embryonic artery. Nature 414, 216–220 (2001).

  36. 36.

    , , & 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).

  37. 37.

    , , & Vessel patterning in the embryo of the zebrafish: guidance by notochord. Dev. Biol. 183, 37–48 (1997).

  38. 38.

    , , , & Radar is required for the establishment of vascular integrity in the zebrafish. Dev. Biol. 251, 105–117 (2002).

  39. 39.

    , , , & Insufficient VEGFA activity in yolk sac endoderm compromises haematopoietic and endothelial differentiation. Development 129, 1881–1892 (2002).

  40. 40.

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

  41. 41.

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

  42. 42.

    , , , & Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development 128, 1717–1730 (2001).

  43. 43.

    , , , & Plasticity of endothelial cells during arterial–venous differentiation in the avian embryo. Development 128, 3359–3370 (2001).

  44. 44.

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

  45. 45.

    , & 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.

  46. 46.

    & Arteries and veins: making a difference with zebrafish. Nature Rev. Genet. 3, 674–682 (2002).

  47. 47.

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

  48. 48.

    , , , & 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.

  49. 49.

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

  50. 50.

    , & Orchestration of angiogenesis and arteriovenous contribution by angiopoietins and vascular endothelial growth factor (VEGF). Proc. Natl Acad. Sci. USA 99, 8219–8224 (2002).

  51. 51.

    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).

  52. 52.

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

  53. 53.

    , , , & 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.

  54. 54.

    , , & Phospholipase C γ-1 is required downstream of vascular endothelial growth factor during arterial development. Genes Dev. 17, 1346–1351 (2003).

  55. 55.

    , , & CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol. 12, 371–384 (2002).

  56. 56.

    , & Notch signaling in vascular development. Arterioscler. Thromb. Vasc. Biol. 23, 543–553 (2003).

  57. 57.

    , & 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).

  58. 58.

    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).

  59. 59.

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

  60. 60.

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

  61. 61.

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

  62. 62.

    & Endothelium — chicken soup for the endoderm. Science 294, 530–531 (2001).

  63. 63.

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

  64. 64.

    & 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).

  65. 65.

    , & The origin and development of retinal astrocytes in the mouse. J. Neurocytol. 21, 530–544 (1992).

  66. 66.

    , , & 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.

  67. 67.

    , & Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000). This study highlights the link between angiogenesis and neurogenesis.

  68. 68.

    , & Induction of astrocyte differentiation by endothelial cells. J. Neurosci. 21, 1538–1547 (2001).

  69. 69.

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

  70. 70.

    , , & Vascular endothelial cell growth factors promote the in vitro development of rat photoreceptor cells. J. Neurosci. 20, 6781–6788 (2000).

  71. 71.

    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.

  72. 72.

    , , & Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. FASEB J. 17, 186–193 (2003).

  73. 73.

    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).

  74. 74.

    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.

  75. 75.

    , , , & Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma. Mol. Cell Neurosci. 13, 450–464 (1999).

  76. 76.

    , , , & Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proc. Natl Acad. Sci. USA 87, 5568–5572 (1990).

  77. 77.

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

  78. 78.

    , , & Irradiation induces neural precursor-cell dysfunction. Nature Med. 8, 955–962 (2002).

  79. 79.

    & 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.

  80. 80.

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

  81. 81.

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

  82. 82.

    , & Eph receptors and ephrins restrict cell intermingling and communication. Nature 400, 77–81 (1999).

  83. 83.

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

  84. 84.

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

  85. 85.

    , , & 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).

  86. 86.

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

  87. 87.

    & 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.

  88. 88.

    , & The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev. 13, 75–85 (2002).

  89. 89.

    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).

  90. 90.

    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).

  91. 91.

    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).

  92. 92.

    , & 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.

  93. 93.

    , & The cadherin superfamily in neural development: diversity, function and interaction with other molecules. Front. Biosci. 8, 306–355 (2003).

  94. 94.

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

  95. 95.

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

  96. 96.

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

  97. 97.

    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).

  98. 98.

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

  99. 99.

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

  100. 100.

    & In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev. Biol. 248, 307–318 (2002).

  101. 101.

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

  102. 102.

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

  103. 103.

    , & Wiring of the brain by a range of guidance cues. Prog. Neurobiol. 68, 393–407 (2002).

  104. 104.

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

  105. 105.

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

  106. 106.

    & Role of Slit proteins in the vertebrate brain. J. Physiol. Paris 96, 91–98 (2002).

  107. 107.

    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.

  108. 108.

    , , & Slit proteins: molecular guidance cues for cells ranging from neurons to leukocytes. Curr. Opin. Genet. Dev. 12, 583–591 (2002).

  109. 109.

    , & Slit is the midline repellent for the robo receptor in Drosophila. Cell 96, 785–794 (1999).

  110. 110.

    , , , & astray, a zebrafish roundabout homolog required for retinal axon guidance. Science 292, 507–510 (2001).

  111. 111.

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

  112. 112.

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

  113. 113.

    & Silencing the siren: guidance cue hierarchies at the CNS midline. Cell 105, 1–4 (2001).

  114. 114.

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

  115. 115.

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

  116. 116.

    , & Regulation of axial patterning of the retina and its topographic mapping in the brain. Curr. Opin. Neurobiol. 13, 57–69 (2003).

  117. 117.

    , , , & Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nature Neurosci. 6, 153–160 (2003).

  118. 118.

    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).

  119. 119.

    & 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.

  120. 120.

    & Semaphorin junction: making tracks toward neural connectivity. Curr. Opin. Neurobiol. 13, 79–89 (2003).

  121. 121.

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

  122. 122.

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

  123. 123.

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

  124. 124.

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

  125. 125.

    & Regulation of angiogenesis by hypoxia: role of the HIF system. Nature Med. 9, 677–684 (2003).

  126. 126.

    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).

  127. 127.

    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).

  128. 128.

    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.

  129. 129.

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

  130. 130.

    , , & Unorthodox angiogenesis in skeletal muscle. Cardiovasc. Res. 49, 634–646 (2001).

  131. 131.

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

  132. 132.

    , & The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis. Development 127, 269–278 (2000).

  133. 133.

    & Cardiovascular ephrinB2 function is essential for embryonic angiogenesis. Development 129, 1397–1410 (2002).

  134. 134.

    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.

  135. 135.

    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).

  136. 136.

    , , , & Semaphorin3a1 regulates angioblast migration and vascular development in zebrafish embryos. Development 130, 3227–3236 (2003).

  137. 137.

    , , , & 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).

  138. 138.

    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.

  139. 139.

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

  140. 140.

    , & Angiotensin's role in renal development. Semin. Nephrol. 17, 492–501 (1997).

  141. 141.

    , , , & Inhibition of angiogenesis by a mouse sprouty protein. J. Biol. Chem. 276, 4128–4133 (2001).

  142. 142.

    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.

  143. 143.

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

  144. 144.

    , & Remodeling of the vascular bed and progressive loss of capillaries in denervated skeletal muscle. Anat. Rec. 258, 292–304 (2000).

  145. 145.

    , & Neuropeptide Y: a novel mechanism for ischemic angiogenesis. Trends Cardiovasc. Med. 13, 86–92 (2003).

  146. 146.

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

  147. 147.

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

  148. 148.

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

  149. 149.

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

  150. 150.

    , , , & Nerve growth factor control of neuronal expression of angiogenetic and vasoactive factors. Proc. Natl Acad. Sci. USA 98, 4160–4165 (2001).

  151. 151.

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

  152. 152.

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

  153. 153.

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

  154. 154.

    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).

  155. 155.

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

  156. 156.

    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.

  157. 157.

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

  158. 158.

    , & VEGF gene transfer for diabetic neuropathy. Hum. Gene Ther. 12, 1593–1594 (2001).

  159. 159.

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

  160. 160.

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

  161. 161.

    , & VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy. J. Anat. 197, 591–605 (2000).

Download references

Author information

Affiliations

  1. Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Katholieke Universiteit Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium.  peter.carmeliet@med.kuleuven.ac.be

    • Peter Carmeliet

Authors

  1. Search for Peter Carmeliet in:

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.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrg1158

Further reading