Astrocyte–endothelial interactions at the blood–brain barrier
TL;DR: Specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood–brain barrier function are explored to lead to the development of new protective and restorative therapies.
Abstract: The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.
Citations
More filters
TL;DR: Astrocyte functions in healthy CNS, mechanisms and functions of reactive astrogliosis and glial scar formation, and ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions are reviewed.
Abstract: Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.
4,075 citations
Cites background from "Astrocyte–endothelial interactions ..."
...The main functional components of the BBB are the endothelial tight junctions [1, 11]....
[...]
...impedes the influx into brain parenchyma of certain molecules on the basis of polarity and size [1, 11]....
[...]
...Numerous lines of in vitro evidence indicate that astrocytes can induce barrier properties in cerebral and other endothelial cells as well as in related epithelial, arguing in favor of a role for astrocytes in BBB induction [1, 11, 17, 208]....
[...]
TL;DR: Understanding of the origins and nature of cancer metastasis and the selection of traits that are advantageous to cancer cells is promoted.
3,863 citations
Cites background from "Astrocyte–endothelial interactions ..."
...The BBB is composed of tightly adjoined endothelial cells that are further lined by basal lamina and astrocyte foot processes (Abbott et al., 2006)....
[...]
TL;DR: The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms are described.
3,783 citations
Cites background or methods from "Astrocyte–endothelial interactions ..."
...The barrier function is not fixed, but can bemodulated and regulated, both in physiology and in pathology (Abbott et al., 2006)....
[...]
...Barrier layers at the key interfaces between blood and neural tissue play a major role in this regulation (Abbott et al., 2006)....
[...]
...Pericytes, microglia and nerve terminals are also closely associated with the endothelium, and play supporting roles in barrier induction, maintenance and function (Abbott et al., 2006; Shimizu et al., 2008; Nakagawa et al., 2009)....
[...]
...In summary the CNS barriers together provide the stable fluid microenvironment that is critical for complex neural function, and protect the CNS from chemical insult and damage....
[...]
...…junctions’ (zonulae occludentes) are a key feature of the BBB and significantly reduce permeation of polar solutes through paracellular diffusional pathways between the endothelial cells from the blood plasma to the brain extracellular fluid (Begley and Brightman, 2003; Wolburg et al., 2009)....
[...]
TL;DR: These findings support developments of new therapeutic approaches for chronic neurodegenerative disorders directed at the blood-brain barrier and other nonneuronal cells of the neurovascular unit.
2,797 citations
Cites background from "Astrocyte–endothelial interactions ..."
...under normal and pathological conditions (Abbott et al., 2006)....
[...]
...If they cross the BBB due to an ischemic injury, intracerebral hemorrhage, trauma, neurodegenerative process, inflammation, or vascular disorder, this typically generates neurotoxic products that can compromise synaptic and neuronal functions (Zlokovic, 2005; Hawkins and Davis, 2005; Abbott et al., 2006)....
[...]
...…cross the BBB due to an ischemic injury, intracerebral hemorrhage, trauma, neurodegenerative process, inflammation, or vascular disorder, this typically generates neurotoxic products that can compromise synaptic and neuronal functions (Zlokovic, 2005; Hawkins and Davis, 2005; Abbott et al., 2006)....
[...]
...Astrocyte-BEC interactions have a major role in regulating brain water and electrolyte metabolism under normal and pathological conditions (Abbott et al., 2006)....
[...]
TL;DR: A novel and critical role for pericytes is indicated in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the blood–brain barrier.
Abstract: The blood–brain barrier is a gatekeeper between the central nervous system and the rest of the body, and is made up of vascular endothelial cells. Previous work upheld the notion that the barrier was formed postnatally as a result of signalling from non-neuronal cells called astrocytes to endothelial cells. Now, two independent studies demonstrate that the barrier is in fact formed during embryogenesis, with the critical factor being the interaction between blood-vessel-surrounding cells called pericytes and epithelial cells. A better understanding of the tight relationship between pericytes, neuroendothelial cells and astrocytes in blood–brain barrier function will contribute to our understanding of the breakdown of the barrier during central nervous system injury and disease. The blood–brain barrier (BBB) is made up of vascular endothelial cells and was thought to have formed postnatally from astrocytes. Two independent studies demonstrate that this barrier forms during embryogenesis, with pericyte/endothelial cell interactions being critical to regulate the BBB during development. A better understanding of the relationship among pericytes, neuroendothelial cells and astrocytes in BBB function will contribute to our understanding of BBB breakdown during central nervous system injury and disease. 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.
2,182 citations
References
More filters
TL;DR: Understanding how BBB TJ might be affected by various factors holds significant promise for the prevention and treatment of neurological diseases.
Abstract: The blood-brain barrier (BBB) is the regulated interface between the peripheral circulation and the central nervous system (CNS). Although originally observed by Paul Ehrlich in 1885, the nature of the BBB was debated well into the 20th century. The anatomical substrate of the BBB is the cerebral microvascular endothelium, which, together with astrocytes, pericytes, neurons, and the extracellular matrix, constitute a "neurovascular unit" that is essential for the health and function of the CNS. Tight junctions (TJ) between endothelial cells of the BBB restrict paracellular diffusion of water-soluble substances from blood to brain. The TJ is an intricate complex of transmembrane (junctional adhesion molecule-1, occludin, and claudins) and cytoplasmic (zonula occludens-1 and -2, cingulin, AF-6, and 7H6) proteins linked to the actin cytoskeleton. The expression and subcellular localization of TJ proteins are modulated by several intrinsic signaling pathways, including those involving calcium, phosphorylation, and G-proteins. Disruption of BBB TJ by disease or drugs can lead to impaired BBB function and thus compromise the CNS. Therefore, understanding how BBB TJ might be affected by various factors holds significant promise for the prevention and treatment of neurological diseases.
2,374 citations
TL;DR: The emerging view is that cerebroVascular dysregulation is a feature not only of cerebrovascular pathologies, such as stroke, but also of neurodegenerative conditions, suchas Alzheimer's disease.
Abstract: The structural and functional integrity of the brain depends on the delicate balance between substrate delivery through blood flow and energy demands imposed by neural activity. Complex cerebrovascular control mechanisms ensure that active brain regions receive an adequate amount of blood, but the nature of these mechanisms remains elusive. Recent findings implicate perivascular neurons, gliovascular interactions and intramural vascular signalling in the control of the cerebral microcirculation. Neurons, astrocytes and vascular cells seem to constitute a functional unit, the primary purpose of which is to maintain the homeostasis of the brain's microenvironment. Alterations of these vascular regulatory mechanisms lead to brain dysfunction and disease. The emerging view is that cerebrovascular dysregulation is a feature not only of cerebrovascular pathologies, such as stroke, but also of neurodegenerative conditions, such as Alzheimer's disease.
2,055 citations
"Astrocyte–endothelial interactions ..." refers background in this paper
...In astrocytes, this can trigger the production of interleukin-6 (IL-6) through activation of nuclear factor-κB (NF-κB) (1)....
[...]
...the brain endothelium forming the blood–brain barrier (BBB) (1), the arachnoid epithelium...
[...]
TL;DR: It is reported that cultured hippocampal astrocytes can respond to glutamate with a prompt and oscillatory elevation of cytoplasmic free calcium, visible through use of the fluorescent calcium indicator fluo-3.
Abstract: The finding that astrocytes possess glutamate-sensitive ion channels hinted at a previously unrecognized signaling role for these cells. Now it is reported that cultured hippocampal astrocytes can respond to glutamate with a prompt and oscillatory elevation of cytoplasmic free calcium, visible through use of the fluorescent calcium indicator fluo-3. Two types of glutamate receptor--one preferring quisqualate and releasing calcium from intracellular stores and the other preferring kainate and promoting surface-membrane calcium influx--appear to be involved. Moreover, glutamate-induced increases in cytoplasmic free calcium frequently propagate as waves within the cytoplasm of individual astrocytes and between adjacent astrocytes in confluent cultures. These propagating waves of calcium suggest that networks of astrocytes may constitute a long-range signaling system within the brain.
1,829 citations
TL;DR: This new research focus addresses an important need in stroke research, provides challenges and opportunities that can be used to therapeutic advantage and is focused on how blood vessels and brain cells communicate with each other.
Abstract: Over the past two decades, research has heavily emphasized basic mechanisms that irreversibly damage brain cells after stroke. Much attention has focused on what makes neurons die easily and what strategies render neurons resistant to ischaemic injury. In the past few years, clinical experience with clot-lysing drugs has confirmed expectations that early reperfusion improves clinical outcome. With recent research emphasizing ways to reduce tissue damage by both vascular and cell-based mechanisms, the spotlight is now shifting towards the study of how blood vessels and brain cells communicate with each other. This new research focus addresses an important need in stroke research, and provides challenges and opportunities that can be used to therapeutic advantage.
1,577 citations
TL;DR: In vivo blockade of glutamate-mediated [Ca2+]i elevations in astrocytes reduced the blood flow increase in the somatosensory cortex during contralateral forepaw stimulation and showed that neuron-to-astrocyte signaling is a key mechanism in functional hyperemia.
Abstract: The cellular mechanisms underlying functional hyperemia--the coupling of neuronal activation to cerebral blood vessel responses--are not yet known. Here we show in rat cortical slices that the dilation of arterioles triggered by neuronal activity is dependent on glutamate-mediated [Ca(2+)](i) oscillations in astrocytes. Inhibition of these Ca(2+) responses resulted in the impairment of activity-dependent vasodilation, whereas selective activation--by patch pipette--of single astrocytes that were in contact with arterioles triggered vessel relaxation. We also found that a cyclooxygenase product is centrally involved in this astrocyte-mediated control of arterioles. In vivo blockade of glutamate-mediated [Ca(2+)](i) elevations in astrocytes reduced the blood flow increase in the somatosensory cortex during contralateral forepaw stimulation. Taken together, our findings show that neuron-to-astrocyte signaling is a key mechanism in functional hyperemia.
1,409 citations