Article

Pericytes are required for blood-brain barrier integrity during embryogenesis

UCSF Department of Anatomy, 513 Parnassus Avenue, HSW1301, San Francisco, California 94143-0452, USA.
Nature (Impact Factor: 42.35). 10/2010; 468(7323):562-6. DOI: 10.1038/nature09513
Source: PubMed

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 disease. Transplantation studies have demonstrated that the BBB is not intrinsic to the endothelial cells, but is induced by interactions with the neural cells. Owing to the close spatial relationship between astrocytes and endothelial cells, it has been hypothesized that astrocytes induce this critical barrier postnatally, but the timing of BBB formation has been controversial. 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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    • "Mural cells on the cerebral vascular tree include arteriolar and venular smooth muscle cells (SMCs) and capillary pericytes (Rouget, 1874). These cells are thought to play important roles in microvascular development, angiogenesis (Armulik et al., 2010; Daneman et al., 2010), and maintenance of the blood brain barrier (Bell et al., 2010), and are implicated in a variety of neuropathological conditions (Bell et al., 2010; Hall et al., 2014; Sagare et al., 2013; Yemisci et al., 2009). It is well known that microvascular smooth muscle regulates vessel diameter and blood flow (Brian et al., 1998; Devor et al., 2007; Ferná ndez-Klett et al., 2010; Kornfield and Newman, 2014; Vanzetta et al., 2005). "
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    ABSTRACT: The precise regulation of cerebral blood flow is critical for normal brain function, and its disruption underlies many neuropathologies. The extent to which smooth muscle-covered arterioles or pericyte-covered capillaries control vasomotion during neurovascular coupling remains controversial. We found that capillary pericytes in mice and humans do not express smooth muscle actin and are morphologically and functionally distinct from adjacent precapillary smooth muscle cells (SMCs). Using optical imaging we investigated blood flow regulation at various sites on the vascular tree in living mice. Optogenetic, whisker stimulation, or cortical spreading depolarization caused microvascular diameter or flow changes in SMC but not pericyte-covered microvessels. During early stages of brain ischemia, transient SMC but not pericyte constrictions were a major cause of hypoperfusion leading to thrombosis and distal microvascular occlusions. Thus, capillary pericytes are not contractile, and regulation of cerebral blood flow in physiological and pathological conditions is mediated by arteriolar SMCs. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 06/2015; DOI:10.1016/j.neuron.2015.06.001 · 15.98 Impact Factor
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    • "During development , the CNS is vascularized by the angiogenic sprouting of vascular networks from the surrounding mesoderm in a precise spatiotemporal manner that differs among species. Which cell type is responsible for BBB differentiation has not yet been clarified: astrocytes have long been considered as the main source of BBB-inducing signals, but barrier induction most likely takes place well before astrocyte differentiation, so there is a probable influence of neuroblast cells or pericytes (Bauer and Bauer, 2000; Armulik et al., 2010; Daneman et al., 2010a). These different structures and cells have different maturation rates across species and across developmental stages, so animal models are not always representative of the human situation in every respect. "
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    ABSTRACT: Disorders of the developing brain represent a major health problem. The neurological manifestations of brain lesions can range from severe clinical deficits to more subtle neurological signs or behavioral problems and learning disabilities, which often become evident many years after the initial damage. These long-term sequelae are due at least in part to central nervous system immaturity at the time of the insult. The blood-brain barrier (BBB) protects the brain and maintains homeostasis. BBB alterations are observed during both acute and chronic brain insults. After an insult, excitatory amino acid neurotransmitters are released, causing reactive oxygen species (ROS)-dependent changes in BBB permeability that allow immune cells to enter and stimulate an inflammatory response. The cytokines, chemokines and other molecules released as well as peripheral and local immune cells can activate an inflammatory cascade in the brain, leading to secondary neurodegeneration that can continue for months or even years and finally contribute to post-insult neuronal deficits. The role of the BBB in perinatal disorders is poorly understood. The inflammatory response, which can be either acute (e.g., perinatal stroke, traumatic brain injury) or chronic (e.g., perinatal infectious diseases) actively modulates the pathophysiological processes underlying brain injury. We present an overview of current knowledge about BBB dysfunction in the developing brain during acute and chronic insults, along with clinical and experimental data.
    Frontiers in Neuroscience 02/2015; 9:40. DOI:10.3389/fnins.2015.00040 · 3.70 Impact Factor
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    • "Findings in murine models of a small vessel brain disease (Daneman et al., 2010; Armulik et al., 2010; Bell et al., 2010, 2012) and human post-mortem AD studies (Fiala et al., 2002; Salloway et al., 2002; Zipser et al., 2007; Ryu and McLarnon, 2009; Hultman et al., 2013; Sengillo et al., 2013) have shown that BBB breakdown leads to tissue accumulation of potentially neurotoxic blood-derived products that normally do not enter the brain but can damage neurons when the vessels become leaky. We show that pericyte injury and possibly early degeneration correlates with increased BBB permeability within the hippocampus , a region known to be affected by pericyte loss and BBB breakdown on post-mortem tissue analysis in AD (Sengillo et al., 2013). "
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    ABSTRACT: The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 01/2015; 85(2):296-302. DOI:10.1016/j.neuron.2014.12.032 · 15.98 Impact Factor
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