The pericyte–glia interface at the blood–brain barrier

Giannoni, Patrizia; Badaut, Jérôme; Dargazanli, Cyril; Maudave, Alexis Fayd’herbe de; Klément, Wendy; Costalat, Vincent; Marchi, Nicola

doi:10.1042/cs20171634

Cited by 69 publications

(55 citation statements)

References 165 publications

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“…Electron microscopy studies showed increased pinocytotic activity, tight junction aberration and a thickening of the basement membrane in epileptic brains [28,29]. In addition to pinocytosis, pericyte-microglia clustering was observed in the epileptic brain, and likely contributes to BBB dysfunction [30,31]. Furthermore, astrocytes undergo morphological and functional alterations after insults and in the epileptic brain.…”

Section: Bbb Structural Alterations In Epilepsymentioning

confidence: 99%

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

Löscher¹,

Friedman

2020

IJMS

164

117

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The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring cell types, including astrocytes and pericytes. In addition to the anatomical characteristics of the BBB, various specific transport systems, enzymes and receptors regulate molecular and cellular traffic across the BBB. While the intact BBB prevents many macromolecules and immune cells from entering the brain, following epileptogenic brain insults the BBB changes its properties. Among BBB alterations, albumin extravasation and diapedesis of leucocytes from blood into brain parenchyma occur, inducing or contributing to epileptogenesis. Furthermore, seizures themselves may modulate BBB functions, permitting albumin extravasation, leading to activation of astrocytes and the innate immune system, and eventually modifications of neuronal networks. BBB alterations following seizures are not necessarily associated with enhanced drug penetration into the brain. Increased expression of multidrug efflux transporters such as P-glycoprotein likely act as a ‘second line defense’ mechanism to protect the brain from toxins. A better understanding of the complex alterations in BBB structure and function following seizures and in epilepsy may lead to novel therapeutic interventions allowing the prevention and treatment of epilepsy as well as other detrimental neuro-psychiatric sequelae of brain injury.

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Section: Bbb Structural Alterations In Epilepsymentioning

confidence: 99%

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

Löscher¹,

Friedman

2020

IJMS

164

117

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“…Despite the implication of the cerebrovasculature in epilepsy, the cellular changes occurring at the outer wall of the BBB remain to be fully defined. Under physiologic conditions, a precise structural arrangement outlines the contact between mural cells and astrocytic end‐feet at the brain endothelium . We previously reported that in response to status epilepticus (SE) and during epileptogenesis, cerebrovascular pericytes or smooth muscle cells undergo redistribution and remodeling, potentially contributing to BBB permeability .…”

Section: Introductionmentioning

confidence: 99%

“…Under physiologic conditions, a precise structural arrangement outlines the contact between mural cells and astrocytic end-feet at the brain endothelium. 5,6 We previously reported that in response to status epilepticus (SE) and during epileptogenesis, cerebrovascular pericytes or smooth muscle cells undergo redistribution and remodeling, potentially contributing to BBB permeability. [7][8][9] During seizures, pericyte damage negatively impacts neurovascular coupling.…”

Section: Introductionmentioning

confidence: 99%

A pericyte‐glia scarring develops at the leaky capillaries in the hippocampus during seizure activity

et al. 2019

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Objective Inflammatory cerebrovascular damage occurs in epilepsy. Here, we tested the hypothesis that a pericyte‐glia scar forms around the outer wall of hippocampal capillaries in a model of temporal lobe epilepsy associated with hippocampal sclerosis. We studied the participation of stromal cells expressing platelet‐derived growth factor receptor beta (PDGFRβ) and extracellular matrix modifications to the perivascular scar during epileptogenesis. Methods We used NG2DsRed/C57BL6 mice and induced status epilepticus (SE) followed by epileptogenesis and spontaneous recurrent seizures (SRS) by means of unilateral intrahippocampal injection of kainic acid (KA). For pharmacological assessment, we used organotypic hippocampal cultures (OHCs) where ictal electrographic activity was elicited by KA or bicuculline. Results NG2DsRed pericytes, GFAP astroglia, and IBA1 microglia are reactive and converge to form a pericapillary multicellular scar in the CA hippocampal regions during epileptogenesis and at SRS. The capillaries are leaky as indicated by fluorescein entering the parenchyma from the peripheral blood. Concomitantly, PDGFRβ transcript and protein levels were significantly increased. Within the regional scar, a fibrotic‐like PDGFRβ mesh developed around the capillaries, peaking at 1 week post‐SE and regressing, but not resolving, at SRS. Abnormal distribution or accumulation of extracellular matrix collagens III/IV occurred in the CA regions during seizure progression. PDGFRβ/DAPI cells were in direct contact with or adjacent to the damaged NG2DsRed pericytes at the capillary interface, consistent with the notion of stromal cell reactivity or fibroblast formation. Inducing electrographic activity in OHCs was sufficient to augment PDGFRβ reactivity around the capillaries. The latter effect was pharmacologically mimicked by treating OHCs with the PDGFRβ agonist PDGF‐BB and it was diminished by the PDGFRβ inhibitor imatinib. Significance The reported multicellular activation and scar are traits of perivascular inflammation and hippocampal sclerosis in experimental epilepsy, with an implication for neurovascular dysfunction. Modulation of PDGFRβ could be exploited to target inflammation in this chronic disease setting.

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“…The BBB consists of a multicellular assembly of endothelial cells, astrocytes, and pericytes, 30 with a main function of separating the circulating blood solutes and cells from the ISF and the brain parenchyma. The BBB consists of a multicellular assembly of endothelial cells, astrocytes, and pericytes, 30 with a main function of separating the circulating blood solutes and cells from the ISF and the brain parenchyma.…”

Section: Macromolecule Accumulation and Neuronal Hyperexcitabilitymentioning

confidence: 99%

“…The blood-brain barrier (BBB) is a functional-anatomic unit and a fundamental segment of the cerebrovascular tree. The BBB consists of a multicellular assembly of endothelial cells, astrocytes, and pericytes, 30 with a main function of separating the circulating blood solutes and cells from the ISF and the brain parenchyma. 31 BBB damage and dysfunction play an important role in generating and sustaining ictal activity.…”

Section: Blood-brain Barrier Impairment Macromolecule Accumulationmentioning

confidence: 99%

Central nervous system lymphatic unit, immunity, and epilepsy: Is there a link?

Noè

Marchi

2019

Epilepsia Open

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Summary The recent definition of a network of lymphatic vessels in the meninges surrounding the brain and the spinal cord has advanced our knowledge on the functional anatomy of fluid movement within the central nervous system (CNS). Meningeal lymphatic vessels along dural sinuses and main nerves contribute to cerebrospinal fluid (CSF) drainage, integrating the cerebrovascular and periventricular routes, and forming a circuit that we here define as the CNS‐lymphatic unit. The latter unit is important for parenchymal waste clearance, brain homeostasis, and the regulation of immune or inflammatory processes within the brain. Disruption of fluid drain mechanisms may promote or sustain CNS disease, conceivably applicable to epilepsy where extracellular accumulation of macromolecules and metabolic by‐products occur in the interstitial and perivascular spaces. Herein we address an emerging concept and propose a theoretical framework on: (a) how a defect of brain clearance of macromolecules could favor neuronal hyperexcitability and seizures, and (b) whether meningeal lymphatic vessel dysfunction contributes to the neuroimmune cross‐talk in epileptic pathophysiology. We propose possible molecular interventions targeting meningeal lymphatic dysfunctions, a potential target for immune‐mediated epilepsy.

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The pericyte–glia interface at the blood–brain barrier

Cited by 69 publications

References 165 publications

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

A pericyte‐glia scarring develops at the leaky capillaries in the hippocampus during seizure activity

Central nervous system lymphatic unit, immunity, and epilepsy: Is there a link?

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