Vascular endothelial cells in the central nervous system (CNS) form a barrier that restricts the movement of molecules and ions between the blood and the brain. This blood–brain barrier (BBB) is crucial to ensure proper neuronal function and protect the CNS from injury and disease1. Transplantation studies have demonstrated that the BBB is not intrinsic to the endothelial cells, but is induced by interactions with the neural cells2. Owing to the close spatial relationship between astrocytes and endothelial cells, it has been hypothesized that astrocytes induce this critical barrier postnatally3, but the timing of BBB formation has been controversial4,5,6,7,8,9. Here we demonstrate that the barrier is formed during embryogenesis as endothelial cells invade the CNS and pericytes are recruited to the nascent vessels, over a week before astrocyte generation. Analysing mice with null and hypomorphic alleles of Pdgfrb, which have defects in pericyte generation, we demonstrate that pericytes are necessary for the formation of the BBB, and that absolute pericyte coverage determines relative vascular permeability. We demonstrate that pericytes regulate functional aspects of the BBB, including the formation of tight junctions and vesicle trafficking in CNS endothelial cells. Pericytes do not induce BBB-specific gene expression in CNS endothelial cells, but inhibit the expression of molecules that increase vascular permeability and CNS immune cell infiltration. These data indicate that pericyte–endothelial cell interactions are critical to regulate the BBB during development, and disruption of these interactions may lead to BBB dysfunction and neuroinflammation during CNS injury and disease.
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Zlokovic, B. V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008)
Stewart, P. A. & Wiley, M. J. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail–chick transplantation chimeras. Dev. Biol. 84, 183–192 (1981)
Janzer, R. C. & Raff, M. C. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325, 253–257 (1987)
Bauer, H. C. et al. Neovascularization and the appearance of morphological characteristics of the blood-brain barrier in the embryonic mouse central nervous system. Brain Res. Dev. Brain Res. 75, 269–278 (1993)
Bolz, S., Farrell, C. L., Dietz, K. & Wolburg, H. Subcellular distribution of glucose transporter (GLUT-1) during development of the blood-brain barrier in rats. Cell Tissue Res. 284, 355–365 (1996)
Butt, A. M., Jones, H. C. & Abbott, N. J. Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study. J. Physiol. (Lond.) 429, 47–62 (1990)
Ek, C. J., Dziegielewska, K. M., Stolp, H. & Saunders, N. R. Functional effectiveness of the blood-brain barrier to small water-soluble molecules in developing and adult opossum (Monodelphis domestica). J. Comp. Neurol. 496, 13–26 (2006)
Hirase, T. et al. Occludin as a possible determinant of tight junction permeability in endothelial cells. J. Cell Sci. 110, 1603–1613 (1997)
Kniesel, U., Risau, W. & Wolburg, H. Development of blood-brain barrier tight junctions in the rat cortex. Brain Res. Dev. Brain Res. 96, 229–240 (1996)
Korn, J., Christ, B. & Kurz, H. Neuroectodermal origin of brain pericytes and vascular smooth muscle cells. J. Comp. Neurol. 442, 78–88 (2002)
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)
Hori, S., Ohtsuki, S., Hosoya, K., Nakashima, E. & Terasaki, T. 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)
Lai, C. H. & Kuo, K. H. The critical component to establish in vitro BBB model: Pericyte. Brain Res. Brain Res. Rev. 50, 258–265 (2005)
Lindahl, P., Johansson, B. R., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997)
Tallquist, M. D., French, W. J. & Soriano, P. Additive effects of PDGF receptor β signaling pathways in vascular smooth muscle cell development. PLoS Biol. 1, e52 (2003)
Hellstrom, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543–554 (2001)
Shepro, D. & Morel, N. M. Pericyte physiology. FASEB J. 7, 1031–1038 (1993)
Lee, S. W., Kim, W. J., Jun, H. O., Choi, Y. K. & Kim, K. W. Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2. Int. J. Mol. Med. 23, 279–284 (2009)
Nag, S., Papneja, T., Venugopalan, R. & Stewart, D. J. Increased angiopoietin2 expression is associated with endothelial apoptosis and blood-brain barrier breakdown. Lab. Invest. 85, 1189–1198 (2005)
Shue, E. H. et al. Plasmalemmal vesicle associated protein-1 (PV-1) is a marker of blood-brain barrier disruption in rodent models. BMC Neurosci. 9, 29 (2008)
Ioannidou, S. et al. An in vitro assay reveals a role for the diaphragm protein PV-1 in endothelial fenestra morphogenesis. Proc. Natl Acad. Sci. USA 103, 16770–16775 (2006)
Wosik, K. et al. Angiotensin II controls occludin function and is required for blood brain barrier maintenance: relevance to multiple sclerosis. J. Neurosci. 27, 9032–9042 (2007)
Gidday, J. M. et al. Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am. J. Physiol. Heart Circ. Physiol. 289, H558–H568 (2005)
He, Z. J., Huang, Z. T., Chen, X. T. & Zou, Z. J. Effects of matrix metalloproteinase 9 inhibition on the blood brain barrier and inflammation in rats following cardiopulmonary resuscitation. Chin. Med. J. (Engl.) 122, 2346–2351 (2009)
Bush, T. G. et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23, 297–308 (1999)
Weidenfeller, C., Svendsen, C. N. & Shusta, E. V. Differentiating embryonic neural progenitor cells induce blood-brain barrier properties. J. Neurochem. 101, 555–565 (2007)
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)
Stenman, J. M. et al. Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322, 1247–1250 (2008)
Motiejunaite, R. & Kazlauskas, A. Pericytes and ocular diseases. Exp. Eye Res. 86, 171–177 (2008)
Cayrol, R. et al. Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system. Nature Immunol. 9, 137–145 (2008)
Watkins, T. A., Emery, B., Mulinyawe, S. & Barres, B. A. Distinct stages of myelination regulated by γ-secretase and astrocytes in a rapidly myelinating CNS coculture system. Neuron 60, 555–569 (2008)
Cahoy, J. D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008)
Chan, J. R. et al. NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes. Neuron 43, 183–191 (2004)
We thank J. Perrino for electron microscopy preparations. Work was supported by grants from the NINDS (R01-NS045621; B.A.B), Myelin Repair Foundation (B.A.B., R.D.), NMSS (Grant-RG3936A7; B.A.B.), UCSF Fellow’s Program (R.D.) and AHA (R.D.).
The authors declare no competing financial interests.
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