Pericyte Biology in Zebrafish

  • Nabila Bahrami
  • Sarah J. ChildsEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1109)


The zebrafish is an outstanding model for studying vascular biology in vivo. Pericytes and vascular smooth muscle cells can be imaged as they associate with vessels and provide stability and integrity to the vasculature. In zebrafish, pericytes associate with the cerebral and trunk vasculature on the second day of development, as assayed by pdgfrβ and notch3 markers. In the head, cerebral pericytes are neural crest derived, except for the pericytes of the hindbrain vasculature, which are mesoderm derived. Similar to the hindbrain, pericytes on the trunk vasculature are also mesoderm derived. Regardless of their location, pericyte development depends on a complex interaction between blood flow and signalling pathways, such as Notch, SONIC HEDGEHOG and BMP signalling, all of which positively regulate pericyte numbers.

Pericyte numbers rapidly increase as development proceeds in order to stabilize both the blood-brain barrier and the vasculature and hence, prevent haemorrhage. Consequently, compromised pericyte development results in compromised vascular integrity, which then evolves into detrimental pathologies. Some of these pathologies have been modelled in zebrafish by inducing mutations in the notch3, foxc1 and foxf2 genes. These zebrafish models provide insights into the mechanisms of disease as associated with pericyte biology. Going forward, these models may be key contributors in elucidating the role of vascular mural cells in regulating vessel diameter and hence, blood flow.


Pericytes Vascular smooth muscle cells Zebrafish pdgfrb notch3 tagln acta2 Neural crest Mesoderm Sclerotome 


  1. 1.
    Alvarez Y et al (2007) Genetic determinants of hyaloid and retinal vasculature in zebrafish. BMC Dev Biol 7:1–17. CrossRefGoogle Scholar
  2. 2.
    Ando K et al (2016) Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish. Development 143(8):1328–1339. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Arciniegas E et al (2000) Intimal thickening involves transdifferentiation of embryonic endothelial cells. Anat Rec 258(1):47–57.<47::AID-AR6>3.0.CO;2-W CrossRefPubMedGoogle Scholar
  4. 4.
    Arnold CR et al (2015) Comparative analysis of genes regulated by Dzip1/iguana and hedgehog in Zebrafish. Dev Dyn 244(2):211–223. CrossRefPubMedGoogle Scholar
  5. 5.
    Bergwerff M, Verberne ME, DeRuiter MC, Poelmann RE, Gittenberger-de Groot AC. (1998) Neural crest cell contribution to the developing circulatory system: implications for vascularmorphology? Feb 9;82(2):221–31 PMID:9468193Google Scholar
  6. 6.
    Bower NI et al (2017) Mural lymphatic endothelial cells regulate meningeal angiogenesis in the zebrafish. Nat Neurosci 20(6):774–783. CrossRefPubMedGoogle Scholar
  7. 7.
    Buchner DA et al (2007) Pak2a mutations cause cerebral hemorrhage in redhead zebrafish. Proc Natl Acad Sci 104(35):13996–14001. CrossRefPubMedGoogle Scholar
  8. 8.
    Bussmann J, Wolfe SA, Siekmann AF (2011) Arterial-venous network formation during brain vascularization involves hemodynamic regulation of chemokine signaling. Development 138(9):1717–1726. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cavanaugh AM, Huang J, Chen J (2015) Two developmentally distinct populations of neural crest cells contribute to the zebra fish heart. Dev Biol Elsevier 404:103–112. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chauhan G et al (2016) Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies. Lancet Neurol 15(7):695–707. CrossRefGoogle Scholar
  11. 11.
    Chen X et al (2017) Cilia control vascular mural cell recruitment in vertebrates. Cell Rep 18(4):1033–1047. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Etchevers HC et al (2001) The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development 128(7):1059–1068. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Fouquet B et al (1997) Vessel patterning in the embryo of the zebrafish: guidance by notochord. Dev Biol 183(1):37–48. CrossRefPubMedGoogle Scholar
  14. 14.
    French CR et al (2014) Mutation of transcription factors FOXC1 and PITX2 causes cerebral small vessel disease. J Clin Investig 124(11):4877–4881. CrossRefPubMedGoogle Scholar
  15. 15.
    Gaengel K et al (2009) Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29(5):630–638. CrossRefGoogle Scholar
  16. 16.
    Galanternik MV et al (2017) A novel perivascular cell population in the zebrafish brain. elife.
  17. 17.
    Goetz JG et al (2014) Endothelial cilia mediate low flow sensing during zebrafish vascular development. Cell Rep 6(5):799–808. CrossRefPubMedGoogle Scholar
  18. 18.
    Goi M, Childs SJ (2016) Patterning mechanisms of the sub-intestinal venous plexus in zebrafish. Dev Biol Elsevier 409(1):114–128. CrossRefPubMedGoogle Scholar
  19. 19.
    Harrison MRM et al (2015) Chemokine-guided angiogenesis directs coronary vasculature formation in zebrafish. Dev Cell. Elsevier Inc. 33(4):442–454. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hayashi H, Kume T (2008) Foxc transcription factors directly regulate DII4 and hey2 expression by interacting with the VEGF-notch signaling pathways in endothelial cells. PLoS One 3(6):1–9. CrossRefGoogle Scholar
  21. 21.
    Hen G et al (2015) Venous-derived angioblasts generate organ-specific vessels during zebrafish embryonic development. Development 142(24):4266–4278. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hirschi KK, D’Amore P a (1996) Pericytes in the mircovasculature. Cardiovasc Res 32:687–698CrossRefGoogle Scholar
  23. 23.
    Hirschi KK, Rohovsky SA, D’Amore PA (1998) PDGF, TGF-B and heterotypic cell-cell interactions mediate the recruitment and differentiation of 10T1/2 cells to a smooth muscle cell fate. J Cell Biol 141(3):805–814. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Jin S-W (2005) Cellular and molecular analyses of vascular tube and lumen formation in zebrafish. Development 132(23):5199–5209. CrossRefPubMedGoogle Scholar
  25. 25.
    Joutel A et al (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710. CrossRefPubMedGoogle Scholar
  26. 26.
    Kallakuri S et al (2015) Endothelial cilia are essential for developmental vascular integrity in zebrafish. J Am Soc Nephrol 26(4):864–875. CrossRefPubMedGoogle Scholar
  27. 27.
    Koenig AL et al (2016) Vegfa signaling promotes zebrafish intestinal vasculature development through endothelial cell migration from the posterior cardinal vein. Dev Biol. Elsevier 411(1):115–127. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kohli V et al (2013) Arterial and venous progenitors of the major axial vessels originate at distinct locations. Dev Cell. United States 25(2):196–206. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kok FO et al (2015) Reverse genetic screening reveals poor correlation between morpholino-induced and mutant phenotypes in zebrafish. Dev Cell. Elsevier Inc. 32(1):97–108. CrossRefPubMedGoogle Scholar
  30. 30.
    Lamont RE et al (2010) Hedgehog signaling via angiopoietin1 is required for developmental vascular stability. Mech Dev 127(3–4):159–168. CrossRefPubMedGoogle Scholar
  31. 31.
    Lawson ND, Weinstein BM (2002) In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev Biol. United States 248(2):307–318CrossRefGoogle Scholar
  32. 32.
    Lei D et al (2017) bmp3 is required for integrity of blood brain barrier by promoting pericyte coverage in zebrafish embryos. Curr Mol Med 17(4):298–303. CrossRefPubMedGoogle Scholar
  33. 33.
    Leveen P, Betsholtz C, Westermark B (1993) Negative trans-acting mechanisms controlling expression of platelet- derived growth factor A and B MRNA in somatic cell hybrids. Exp Cell Res:283–289 Available at:
  34. 34.
    Liu J et al (2007) A betaPix Pak2a signaling pathway regulates cerebral vascular stability in zebrafish. Proc Natl Acad Sci 104(35):13990–13995. CrossRefPubMedGoogle Scholar
  35. 35.
    Miano JM et al (2006) Ultrastructure of zebrafish dorsal aortic cells. Zebrafish 3(4):455–463. CrossRefPubMedGoogle Scholar
  36. 36.
    Monet-Leprêtre M et al (2013) Abnormal recruitment of extracellular matrix proteins by excess Notch3ECD: a new pathomechanism in CADASIL. Brain 136(6):1830–1845. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Pitulescu ME, Adams RH (2014) Regulation of signaling interactions and receptor endocytosis in growing blood vessels. Cell Adhes Migr 8(4):366–377. CrossRefGoogle Scholar
  38. 38.
    Quillien A et al (2014) Distinct notch signaling outputs pattern the developing arterial system. Development 141(7):1544–1552. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Reischauer S et al (2016) Cloche is a bHLH-PAS transcription factor that drives haemato-vascular specification. Nature. Nature Publishing Group 535(7611):294–298. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Reyahi A et al (2015) Foxf2 is required for brain pericyte differentiation and development and maintenance of the blood-brain barrier. Dev Cell 34(1):19–32. CrossRefPubMedGoogle Scholar
  41. 41.
    Santoro MM et al (2007) Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasis. Nat Genet 39(11):1397–1402. CrossRefPubMedGoogle Scholar
  42. 42.
    Santoro MM, Pesce G, Stainier DY (2009) Characterization of vascular mural cells during zebrafish development. Mech Dev 126(8–9):638–649. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Seo S et al (2006) The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Dev Biol 294(2):458–470. CrossRefPubMedGoogle Scholar
  44. 44.
    Stainier DY et al (1995) Cloche, an early acting zebrafish gene, is required by both the endothelial and hematopoietic lineages. Development 121(10):3141–3150PubMedGoogle Scholar
  45. 45.
    Stainier DY et al (1996) Mutations affecting the formation and function of the cardiovascular system in the zebrafish embryo. Development. England 123:285–292PubMedGoogle Scholar
  46. 46.
    Stratman AN et al (2017) Interactions between mural cells and endothelial cells stabilize the developing zebrafish dorsal aorta. Development 144(1):115–127. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Ulrich F et al (2016) Reck enables cerebrovascular development by promoting canonical Wnt signaling. Development 143(6):1055–1055. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    De Val S, Black BL (2009) Transcriptional control of endothelial cell development. Dev Cell Elsevier Inc. 16(2):180–195. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Vanhollebeke B et al (2015) Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis. elife:1–25.
  50. 50.
    Der Wang W et al (2011) Tfap2a and Foxd3 regulate early steps in the development of the neural crest progenitor population. Dev Biol. Elsevier Inc. 360(1):173–185. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Wang Y et al (2014) Notch3 establishes brain vascular integrity by regulating pericyte number. Development 141(2):307–317. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Whitesell TR et al (2014) An α-smooth muscle actin (acta2/αsma) zebrafish transgenic line marking vascular mural cells and visceral smooth muscle cells. PLoS One United States 9(3):e90590. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Wiens KM et al (2010) Platelet-derived growth factor receptor β is critical for zebrafish intersegmental vessel formation. PLoS One 5(6).
  54. 54.
    Xu K, Cleaver O (2011) Tubulogenesis during blood vessel formation. Semin Cell Dev Biol 22(9):993–1004. CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyAlberta Children’s Hospital Research Institute, University of CalgaryCalgaryCanada

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