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Remodeling and Recovery in the Neurovascular Unit

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 27910

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Special Issue Editors

Dr. Ken Arai

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Guest Editor

Harvard Medical School, Massachusetts General Hospital, Boston, USA
Interests: stroke; dementia; white matter; oligodendrocyte; neurovascular unit

Dr. Kazuto Masamoto

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Guest Editor

The University of Electro-Communications, Tokyo, Japan
Interests: neurovascular coupling; cerebral circulation; imaging

Dr. Elga Esposito

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Guest Editor

Harvard Medical School, Massachusetts General Hospital, Boston, USA
Interests: stroke; circadian rhythm; brain–lymphatic crosstalk; glia

Dr. Wenlu Li

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Guest Editor

Harvard Medical School, Massachusetts General Hospital, Boston, USA
Interests: stroke; blood–brain barrier; glia–neuron interaction; cell differentiation

Dr. Emiri T. Mandeville

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Guest Editor

Harvard Medical School, Massachusetts General Hospital, Boston, USA
Interests: MRI; stroke; traumatic brain injury; neurovascular unit

Special Issue Information

Dear Colleagues,

In 2001, the concept of the neurovascular unit was proposed at a workshop of the National Institute of Neurological Disorders and Stroke to encourage a broader approach in stroke research. Fundamentally, this concept emphasizes that all compartments of the neurovascular unit (e.g., neuronal, glial, vascular) must be assessed to understand the pathological mechanism of stroke because stroke may not be a purely “neuron death” disease. This idea stems from the fact that cell–cell interaction among different types of cells helps to maintain brain homeostasis under physiological conditions, whereas these trophic couplings are disturbed after stroke, contributing to pathophysiology. In addition, accumulating data now suggest that even under stroke conditions, some of these cell–cell signaling mechanisms may also mediate parallel processes of neurovascular remodeling and repairing, including compensatory neurogenesis, angiogenesis, and oligodendrogenesis.

Two decades have passed since the concept of the neurovascular unit was first introduced, and the neurovascular unit has now grown far beyond its original roots in stroke. The idea that cell–cell signaling underlies both brain function and dysfunction is now relatively well accepted and helps us to examine pathological mechanisms of several central nervous system (CNS) disorders. This Special Issue focuses on the research topic of mechanisms of neurovascular remodeling and repair after brain injury, and we welcome both original research and review manuscripts.

Dr. Ken Arai
Dr. Kazuto Masamoto
Dr. Elga Esposito
Dr. Wenlu Li
Dr. Emiri T. Mandeville
Guest Editors

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Keywords

angiogenesis
brain repair
cell differentiation
cell proliferation
glia–neuron interaction
neurogenesis
neurovascular coupling
neurovascular unit
oligodendrogenesis
stroke

Published Papers (9 papers)

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Research

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13 pages, 1976 KiB

Open AccessArticle

Functional Deficiency of Interneurons and Negative BOLD fMRI Response

by Daniil P. Aksenov, Limin Li, Natalya A. Serdyukova, David A. Gascoigne, Evan D. Doubovikov and Alexander Drobyshevsky

Cells 2023, 12(5), 811; https://doi.org/10.3390/cells12050811 - 6 Mar 2023

Cited by 1 | Viewed by 1483

Abstract

The functional deficiency of the inhibitory system typically appears during development and can progress to psychiatric disorders or epilepsy, depending on its severity, in later years. It is known that interneurons, the major source of GABAergic inhibition in the cerebral cortex, can make direct connections with arterioles and participate in the regulation of vasomotion. The goal of this study was to mimic the functional deficiency of interneurons through the use of localized microinjections of the GABA antagonist, picrotoxin, in such a concentration that it did not elicit epileptiform neuronal activity. First, we recorded the dynamics of resting-state neuronal activity in response to picrotoxin injections in the somatosensory cortex of an awake rabbit; second, we assessed the altered neuronal and hemodynamic responses to whisker stimulation using BOLD fMRI and electrophysiology recordings; third, we evaluated brain tissue oxygen levels before and after picrotoxin injection. Our results showed that neuronal activity typically increased after picrotoxin administration, the BOLD responses to stimulation became negative, and the oxygen response was nearly abolished. Vasoconstriction during the resting baseline was not observed. These results indicate that picrotoxin provoked imbalanced hemodynamics either due to increased neuronal activity, decreased vascular response, or a combination of both. Full article

(This article belongs to the Special Issue Remodeling and Recovery in the Neurovascular Unit)

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15 pages, 2684 KiB

Open AccessArticle

Transcutaneous Auricular Vagus Nerve Stimulation Enhances Cerebrospinal Fluid Circulation and Restores Cognitive Function in the Rodent Model of Vascular Cognitive Impairment

by Seunghwan Choi, Dong Cheol Jang, Geehoon Chung and Sun Kwang Kim

Cells 2022, 11(19), 3019; https://doi.org/10.3390/cells11193019 - 27 Sep 2022

Cited by 9 | Viewed by 3184

Abstract

Vascular cognitive impairment (VCI) is a common sequela of cerebrovascular disorders. Although transcutaneous auricular vagus nerve stimulation (taVNS) has been considered a complementary treatment for various cognitive disorders, preclinical data on the effect of taVNS on VCI and its mechanism remain ambiguous. To measure cerebrospinal fluid (CSF) circulation during taVNS, we used in vivo two-photon microscopy with CSF and vasculature tracers. VCI was induced by transient bilateral common carotid artery occlusion (tBCCAO) surgery in mice. The animals underwent anesthesia, off-site stimulation, or taVNS for 20 min. Cognitive tests, including the novel object recognition and the Y-maze tests, were performed 24 h after the last treatment. The long-term treatment group received 6 days of treatment and was tested on day 7; the short-term treatment group received 2 days of treatment and was tested 3 days after tBCCAO surgery. CSF circulation increased remarkably in the taVNS group, but not in the anesthesia-control or off-site-stimulation-control groups. The cognitive impairment induced by tBCCAO was significantly restored after both long- and short-term taVNS. In terms of effects, both long- and short-term stimulations showed similar recovery effects. Our findings provide evidence that taVNS can facilitate CSF circulation and that repetitive taVNS can ameliorate VCI symptoms. Full article

(This article belongs to the Special Issue Remodeling and Recovery in the Neurovascular Unit)

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15 pages, 4001 KiB

Open AccessArticle

Behind the Wall—Compartment-Specific Neovascularisation during Post-Stroke Recovery in Mice

by Anja Kolbinger, Roxane Isabelle Kestner, Lara Jencio, Tim J. Schäufele, Rajkumar Vutukuri, Waltraud Pfeilschifter and Klaus Scholich

Cells 2022, 11(10), 1659; https://doi.org/10.3390/cells11101659 - 17 May 2022

Cited by 5 | Viewed by 2201

Abstract

Ischemic stroke is a highly prevalent vascular disease leading to oxygen- and glucose deprivation in the brain. In response, ischemia-induced neovascularization occurs, which is supported by circulating CD34⁺ endothelial progenitor cells. Here, we used the transient middle cerebral artery occlusion (tMCAO) mouse model to characterize the spatio-temporal alterations within the ischemic core from the acute to the chronic phase using multiple-epitope-ligand cartography (MELC) for sequential immunohistochemistry. We found that around 14 days post-stroke, significant angiogenesis occurs in the ischemic core, as determined by the presence of CD31⁺/CD34⁺ double-positive endothelial cells. This neovascularization was accompanied by the recruitment of CD4⁺ T-cells and dendritic cells as well as IBA1⁺ and IBA1⁻ microglia. Neighborhood analysis identified, besides pericytes only for T-cells and dendritic cells, a statistically significant distribution as direct neighbors of CD31⁺/CD34⁺ endothelial cells, suggesting a role for these cells in aiding angiogenesis. This process was distinct from neovascularization of the peri-infarct area as it was separated by a broad astroglial scar. At day 28 post-stroke, the scar had emerged towards the cortical periphery, which seems to give rise to a neuronal regeneration within the peri-infarct area. Meanwhile, the ischemic core has condensed to a highly vascularized subpial region adjacent to the leptomeningeal compartment. In conclusion, in the course of chronic post-stroke regeneration, the astroglial scar serves as a seal between two immunologically active compartments—the peri-infarct area and the ischemic core—which exhibit distinct processes of neovascularization as a central feature of post-stroke tissue remodeling. Based on our findings, we propose that neovascularization of the ischemic core comprises arteriogenesis as well as angiogenesis originating from the leptomenigeal vasculature. Full article

(This article belongs to the Special Issue Remodeling and Recovery in the Neurovascular Unit)

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17 pages, 3493 KiB

Open AccessArticle

Dual Effects of Korean Red Ginseng on Astrocytes and Neural Stem Cells in Traumatic Brain Injury: The HO-1–Tom20 Axis as a Putative Target for Mitochondrial Function

by Minsu Kim, Sunhong Moon, Hui Su Jeon, Sueun Kim, Seong-Ho Koh, Mi-Sook Chang, Young-Myeong Kim and Yoon Kyung Choi

Cells 2022, 11(5), 892; https://doi.org/10.3390/cells11050892 - 4 Mar 2022

Cited by 9 | Viewed by 3437

Abstract

Astrocytes display regenerative potential in pathophysiologic conditions. In our previous study, heme oxygenase-1 (HO-1) promoted astrocytic mitochondrial functions in mice via the peroxisome-proliferator-activating receptor-γ coactivator-1α (PGC-1α) pathway on administering Korean red ginseng extract (KRGE) after traumatic brain injury (TBI). In this study, KRGE promoted astrocytic mitochondrial functions, assessed with oxygen consumption and adenosine triphosphate (ATP) production, which could be regulated by the translocase of the outer membrane of mitochondria 20 (Tom20) pathway with a PGC-1α-independent pathway. The HO-1–Tom20 axis induced an increase in mitochondrial functions, detected with cytochrome c oxidase subunit 2 and cytochrome c. HO-1 crosstalk with nicotinamide phosphoribosyltransferase was concomitant with the upregulated nicotinamide adenine dinucleotide (NAD)/NADH ratio, thereby upregulating NAD-dependent class I sirtuins. In adult neural stem cells (NSCs), KRGE-treated, astrocyte-conditioned media increased oxygen consumption and Tom20 levels through astrocyte-derived HO-1. HO inactivation by Sn(IV) protoporphyrin IX dichloride in TBI mice administered KRGE decreased neuronal markers, together with Tom20. Thus, astrocytic HO-1 induced astrocytic mitochondrial functions. HO-1-related, astrocyte-derived factors may also induce neuronal differentiation and mitochondrial functions of adult NSCs after TBI. KRGE-mediated astrocytic HO-1 induction may have a key role in repairing neurovascular function post-TBI in peri-injured regions by boosting astrocytic and NSC mitochondrial functions. Full article

(This article belongs to the Special Issue Remodeling and Recovery in the Neurovascular Unit)

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Review

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39 pages, 1297 KiB

Open AccessReview

Remodeling of the Neurovascular Unit Following Cerebral Ischemia and Hemorrhage

by Yoshimichi Sato, Jaime Falcone-Juengert, Teiji Tominaga, Hua Su and Jialing Liu

Cells 2022, 11(18), 2823; https://doi.org/10.3390/cells11182823 - 9 Sep 2022

Cited by 14 | Viewed by 3659

Abstract

Formulated as a group effort of the stroke community, the transforming concept of the neurovascular unit (NVU) depicts the structural and functional relationship between brain cells and the vascular structure. Composed of both neural and vascular elements, the NVU forms the blood–brain barrier that regulates cerebral blood flow to meet the oxygen demand of the brain in normal physiology and maintain brain homeostasis. Conversely, the dysregulation and dysfunction of the NVU is an essential pathological feature that underlies neurological disorders spanning from chronic neurodegeneration to acute cerebrovascular events such as ischemic stroke and cerebral hemorrhage, which were the focus of this review. We also discussed how common vascular risk factors of stroke predispose the NVU to pathological changes. We synthesized existing literature and first provided an overview of the basic structure and function of NVU, followed by knowledge of how these components remodel in response to ischemic stroke and brain hemorrhage. A greater understanding of the NVU dysfunction and remodeling will enable the design of targeted therapies and provide a valuable foundation for relevant research in this area. Full article

(This article belongs to the Special Issue Remodeling and Recovery in the Neurovascular Unit)

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13 pages, 1211 KiB

Open AccessReview

T-Lymphocyte Interactions with the Neurovascular Unit: Implications in Intracerebral Hemorrhage

by Samuel X. Shi, Samuel J. Vodovoz, Yuwen Xiu, Ning Liu, Yinghua Jiang, Prasad V. G. Katakam, Gregory Bix, Aaron S. Dumont and Xiaoying Wang

Cells 2022, 11(13), 2011; https://doi.org/10.3390/cells11132011 - 24 Jun 2022

Cited by 5 | Viewed by 2147

Abstract

In the pathophysiology of hemorrhagic stroke, the perturbation of the neurovascular unit (NVU), a functional group of the microvascular and brain intrinsic cellular components, is implicated in the progression of secondary injury and partially informs the ultimate patient outcome. Given the broad NVU functions in maintaining healthy brain homeostasis through its maintenance of nutrients and energy substrates, partitioning central and peripheral immune components, and expulsion of protein and metabolic waste, intracerebral hemorrhage (ICH)-induced dysregulation of the NVU directly contributes to numerous destructive processes in the post-stroke sequelae. In ICH, the damaged NVU precipitates the emergence and evolution of perihematomal edema as well as the breakdown of the blood–brain barrier structural coherence and function, which are critical facets during secondary ICH injury. As a gateway to the central nervous system, the NVU is among the first components to interact with the peripheral immune cells mobilized toward the injured brain. The release of signaling molecules and direct cellular contact between NVU cells and infiltrating leukocytes is a factor in the dysregulation of NVU functions and further adds to the acute neuroinflammatory environment of the ICH brain. Thus, the interactions between the NVU and immune cells, and their reverberating consequences, are an area of increasing research interest for understanding the complex pathophysiology of post-stroke injury. This review focuses on the interactions of T-lymphocytes, a major cell of the adaptive immunity with expansive effector function, with the NVU in the context of ICH. In cataloging the relevant clinical and experimental studies highlighting the synergistic actions of T-lymphocytes and the NVU in ICH injury, this review aimed to feature emergent knowledge of T cells in the hemorrhagic brain and their diverse involvement with the neurovascular unit in this disease. Full article

(This article belongs to the Special Issue Remodeling and Recovery in the Neurovascular Unit)

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16 pages, 26338 KiB

Open AccessReview

Reciprocal Interactions between Oligodendrocyte Precursor Cells and the Neurovascular Unit in Health and Disease

by Friederike Pfeiffer

Cells 2022, 11(12), 1954; https://doi.org/10.3390/cells11121954 - 17 Jun 2022

Cited by 4 | Viewed by 2892

Abstract

Oligodendrocyte precursor cells (OPCs) are mostly known for their capability to differentiate into oligodendrocytes and myelinate axons. However, they have been observed to frequently interact with cells of the neurovascular unit during development, homeostasis, and under pathological conditions. The functional consequences of these interactions are largely unclear, but are increasingly studied. Although OPCs appear to be a rather homogenous cell population in the central nervous system (CNS), they present with an enormous potential to adapt to their microenvironment. In this review, it is summarized what is known about the various roles of OPC-vascular interactions, and the circumstances under which they have been observed. Full article

(This article belongs to the Special Issue Remodeling and Recovery in the Neurovascular Unit)

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16 pages, 1417 KiB

Open AccessEditor’s ChoiceReview

Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit

by Shinichi Takahashi

Cells 2022, 11(5), 813; https://doi.org/10.3390/cells11050813 - 25 Feb 2022

Cited by 27 | Viewed by 5835

Abstract

The neurovascular unit (NVU) is a conceptual framework that has been proposed to better explain the relationships between the neural cells and blood vessels in the human brain, focused mainly on the brain gray matter. The major components of the NVU are the neurons, astrocytes (astroglia), microvessels, pericytes, and microglia. In addition, we believe that oligodendrocytes should also be included as an indispensable component of the NVU in the white matter. Of all these components, astrocytes in particular have attracted the interest of researchers because of their unique anatomical location; these cells are interposed between the neurons and the microvessels of the brain. Their location suggests that astrocytes might regulate the cerebral blood flow (CBF) in response to neuronal activity, so as to ensure an adequate supply of glucose and oxygen to meet the metabolic demands of the neurons. In fact, the adult human brain, which accounts for only 2% of the entire body weight, consumes approximately 20–25% of the total amount of glucose and oxygen consumed by the whole body. The brain needs a continuous supply of these essential energy sources through the CBF, because there are practically no stores of glucose or oxygen in the brain; both acute and chronic cessation of CBF can adversely affect brain functions. In addition, another important putative function of the NVU is the elimination of heat and waste materials produced by neuronal activity. Recent evidence suggests that astrocytes play pivotal roles not only in supplying glucose, but also fatty acids and amino acids to neurons. Loss of astrocytic support can be expected to lead to malfunction of the NVU as a whole, which underlies numerous neurological disorders. In this review, we shall focus on historical and recent findings with regard to the metabolic contributions of astrocytes in the NVU. Full article

(This article belongs to the Special Issue Remodeling and Recovery in the Neurovascular Unit)

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Other

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16 pages, 4666 KiB

Open AccessProtocol

High Resolution Multiplex Confocal Imaging of the Neurovascular Unit in Health and Experimental Ischemic Stroke

by Jeffrey J. Lochhead, Erica I. Williams, Elizabeth S. Reddell, Emma Dorn, Patrick T. Ronaldson and Thomas P. Davis

Cells 2023, 12(4), 645; https://doi.org/10.3390/cells12040645 - 17 Feb 2023

Cited by 1 | Viewed by 1941

Abstract

The neurovascular unit (NVU) is an anatomical group of cells that establishes the blood–brain barrier (BBB) and coordinates cerebral blood flow in association with neuronal function. In cerebral gray matter, cellular constituents of the NVU include endothelial cells and associated pericytes, astrocytes, neurons, and microglia. Dysfunction of the NVU is a common feature of diseases that affect the CNS, such as ischemic stroke. High-level evaluation of these NVU changes requires the use of imaging modalities that can enable the visualization of various cell types under disease conditions. In this study, we applied our confocal microscopy strategy using commercially available labeling reagents to, for the first time, simultaneously investigate associations between endothelial cells, the vascular basal lamina, pericytes, microglia, astrocytes and/or astrocyte end-feet, and neurites in both healthy and ischemic brain tissue. This allowed us to demonstrate ischemia-induced astrocyte activation, neurite loss, and microglial migration toward blood vessels in a single confocal image. Furthermore, our labeling cocktail enabled a precise quantification of changes in neurites and astrocyte reactivity, thereby showing the relationship between different NVU cellular constituents in healthy and diseased brain tissue. The application of our imaging approach for the simultaneous visualization of multiple NVU cell types provides an enhanced understanding of NVU function and pathology, a state-of-the-art advancement that will facilitate the development of more effective treatment strategies for diseases of the CNS that exhibit neurovascular dysfunction, such as ischemic stroke. Full article

(This article belongs to the Special Issue Remodeling and Recovery in the Neurovascular Unit)

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