Pericytes regulate the blood–brain barrier

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Abstract

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.

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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.

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Gene Expression Omnibus

Data deposits

Our microarray data have been deposited in NCBIs Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO series accession number GSE15892.

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Acknowledgements

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.

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The authors declare no competing financial interests.

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

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