Pericytes regulate the blood–brain barrier

Article metrics


The blood–brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS)1. The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport2. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes3, but the relative contribution of these different components to the BBB remains largely unknown1,3. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Pericyte coverage correlates with BBB integrity.
Figure 2: Pericyte-deficient mice show accumulation of intravenously injected tracers in the brain parenchyma and in the endothelium.
Figure 3: Imatinib treatment abolishes accumulation of intravenously injected tracers in the brain parenchyma in pericyte-deficient mutants.
Figure 4: Transcript profiling of brain microvasculature and characterization of the polarization defect of astrocyte end-feet in pericyte-deficient mutants.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Our microarray data have been deposited in NCBIs Gene Expression Omnibus ( and are accessible through GEO series accession number GSE15892.


  1. 1

    Abbott, N. J., Rönnbäck, L. & Hansson, E. Astrocyte-endothelial interactions at the blood-brain barrier. Nature Rev. Neurosci. 7, 41–53 (2006)

  2. 2

    Reese, T. S. & Karnovsky, M. J. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol. 34, 207–217 (1967)

  3. 3

    Bernacki, J. et al. Physiology and pharmacological role of the blood-brain barrier. Pharmacol. Rep. 60, 600–622 (2008)

  4. 4

    Enge, M. et al. Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J. 21, 4307–4316 (2002)

  5. 5

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

  6. 6

    Levéen, P. et al. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 8, 1875–1887 (1994)

  7. 7

    Soriano, P. Abnormal kidney development and hematological disorders in PDGF β-receptor mutant mice. Genes Dev. 8, 1888–1896 (1994)

  8. 8

    Lindblom, P. et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003)

  9. 9

    Tidhar, A. et al. A novel transgenic marker for migrating limb muscle precursors and for vascular smooth muscle cells. Dev. Dyn. 220, 60–73 (2001)

  10. 10

    Lindahl, P. et al. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997)

  11. 11

    Hellström, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543–554 (2001)

  12. 12

    Moos, T. & Møllgård, K. Cerebrovascular permeability to azo dyes and plasma proteins in rodents of different ages. Neuropathol. Appl. Neurobiol. 19, 120–127 (1993)

  13. 13

    Dejana, E., Tournier-Lasserve, E. & Weinstein, B. M. The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev. Cell 16, 209–221 (2009)

  14. 14

    Taddei, A. et al. Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nature Cell Biol. 10, 923–934 (2008)

  15. 15

    Stenman, J. M. et al. Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322, 1247–1250 (2008)

  16. 16

    Liebner, S. et al. Wnt/beta-catenin signaling controls development of the blood-brain barrier. J. Cell Biol. 183, 409–417 (2008)

  17. 17

    Su, E. J. et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nature Med. 14, 731–737 (2008)

  18. 18

    Bondjers, C. et al. Microarray analysis of blood microvessels from PDGF-B and PDGF-Rβ mutant mice identifies novel markers for brain pericytes. FASEB J. 20, 1703–1705 (2006)

  19. 19

    Wallgard, E. et al. Identification of a core set of 58 gene transcripts with broad and specific expression in the microvasculature. Arterioscler. Thromb. Vasc. Biol. 28, 1469–1476 (2008)

  20. 20

    He, L. et al. The glomerular transcriptome and a predicted protein-protein interaction network. J. Am. Soc. Nephrol. 19, 260–268 (2008)

  21. 21

    Wolburg, H. et al. Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood-brain barrier. Neuroscientist 15, 180–193 (2009)

  22. 22

    Janzer, R. C. & Raff, M. C. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325, 253–257 (1987)

  23. 23

    Hayashi, Y. et al. Induction of various blood-brain barrier properties in non-neural endothelial cells by close apposition to co-cultured astrocytes. Glia 19, 13–26 (1997)

  24. 24

    Sobue, K. et al. Induction of blood-brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci. Res. 35, 155–164 (1999)

  25. 25

    Daneman, R. et al. Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc. Natl Acad. Sci. USA 106, 641–646 (2009)

  26. 26

    Hori, S. et al. A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro . J. Neurochem. 89, 503–513 (2004)

  27. 27

    Dohgu, S. et al. Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-β production. Brain Res. 1038, 208–215 (2005)

  28. 28

    Kisanuki, Y. Y. et al. Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo . Dev. Biol. 230, 230–242 (2001)

  29. 29

    Novak, A. et al. Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis 28, 147–155 (2000)

  30. 30

    Zambrowicz, B. P. et al. Disruption of overlapping transcripts in the ROSA βgeo 26 gene trap strain leads to widespread expression of β-galactosidase in mouse embryos and hematopoietic cells. Proc. Natl Acad. Sci. USA 94, 3789–3794 (1997)

  31. 31

    Karnovsky, M. J. The ultrastructural basis of capillary permeability studied with peroxidase as a tracer. J. Cell Biol. 35, 213–236 (1967)

  32. 32

    Bender, A. et al. Creatine improves health and survival of mice. Neurobiol. Aging 29, 1404–1411 (2008)

  33. 33

    Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995)

Download references


We thank U. Eriksson and members of the Betsholtz laboratory for discussion, P. Soriano, L. Sorokin and R. Hallman for reagents, and S. Kamph and the Scheele animal house for technical assistance. This work was supported by the Leducq Foundation, the Swedish Governmental Agency for Innovation Systems (Vinnova), the EU Fp6 Program Lymphangiogenomics, the Swedish Cancer Society and Research Council, the Knut and Alice Wallenberg, Inga-Britt and Arne Lundberg, and Torsten and Ragnar Söderberg Foundations.

Author information

A.A. and C.B. conceived and designed the project. A.A., G.G., M.M., M.H.N., E.W., C.N., L.H., J.N., P.L., K.S. and B.R.J. performed experiments; C.B. and A.A. wrote the manuscript with significant input from M.M., G.G. and M.H.N. G.G. and M.M. contributed equally to the study.

Correspondence to Annika Armulik or Christer Betsholtz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-12 with legends, Supplementary Methods and Supplementary Tables 1-3. (PDF 20465 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Armulik, A., Genové, G., Mäe, M. et al. Pericytes regulate the blood–brain barrier. Nature 468, 557–561 (2010) doi:10.1038/nature09522

Download citation

Further reading


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.