Pericytes are required for blood–brain barrier integrity during embryogenesis

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Abstract

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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Figure 1: Time course of cell generation and BBB development in the rat cerebral cortex.
Figure 2: Pericytes are required for BBB formation.
Figure 3: Pericytes regulate structural aspects of the BBB.
Figure 4: Vascular expression of LAMs in Pdgfrb −/− mice.

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Acknowledgements

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.).

Author information

R.D. and B.A.B. designed experiments and wrote the manuscript. R.D., L.Z. and A.A.K. performed and analysed experiments.

Correspondence to Richard Daneman.

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The authors declare no competing financial interests.

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