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Blood-Brain Barrier and Blood-Retinal Barrier Diseases: Molecular Mechanisms, Patterns, and New Concepts

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 17102

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Special Issue Editors

Dr. Carmelina Daniela Anfuso

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Guest Editor

Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, School of Medicine, University of Catania, 95123 Catania, Italy
Interests: blood brain barrier; blood retinal barrier; endothelial cells; pericytes; inflammation; phospholipase A2; diabetic retinopathy; cancer

Dr. Gabriella Lupo

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Guest Editor

Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, School of Medicine, University of Catania, 95123 Catania, Italy
Interests: human retinal endothelial cells; metastatic uveal melanoma; melanogenesis

Special Issue Information

Dear Colleagues,

The brain and retina are delicate organs because both neuropils require highly specialized environments to function properly. The vascular blood and inner retinal barriers (BBB and iBRB) represent the brain/retina’s main interface with their respective external environments at which these processes are mostly controlled. In the normal brain and retina, microvascular biology results overall from interactions of endothelial cells with the basement membrane and neighboring glial cells, such as perivascular pericytes, microglia, astrocytes, Müller cells (in retina), as well as neurons. These cells contribute to creating a selective permeability to prevent the entry of molecules and cells between systemic circulation and nervous tissues (the so-called neurovascular unit). This feature relies on a low rate of transcytosis through both of these barriers and the presence of junctional complexes, adherens and tight junctions. Dysfunctions in the BBB and BRB occur in a large number of diseases, including multiple sclerosis, epilepsy, Alzheimer’s disease, stroke, glaucoma, diabetic retinopathy, age-related macular degeneration, retinal inflammatory diseases and tumors, and their consequent breakdown causes ion dysregulation, edema, and neuroinflammation. Therapeutic drugs for protection these barriers need to aim for the reinforcement of endothelial barrier properties, the blockage of intracellular signaling pathways leading to BBB/BRB dysfunction, transendothelial electrical resistance restoration and inhibition of the release of inflammatory mediators from neurovascular unit cells. Here, we aim to gather contributions from basic researchers and clinical scientists aimed at indicating, in both in in vivo and in vitro model systems, the following:

New biochemical and physiological mechanisms and innovative target molecules or biomarkers related to microvessel pathology;
New signal pathways involved in the breakdown of both barriers;
The promotion of translational and integrated approaches aimed at the prevention and treatment of cerebral and retinal microvessel pathologies;
Novel and safe nanoparticle systems and new natural compounds suitable for the management of microvascular-unit-related diseases;
Innovative cellular therapies.

The Special Issue is also aimed at collecting reviews on the state-of-art of research on this topic to date.

Dr. Carmelina Daniela Anfuso
Dr. Gabriella Lupo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Blood Brain Barrier (BBB)
Blood Retinal Barrier (BRB)
vascular blood
microvascular biology
brain
retina
neighboring glial cells
barriers protection
microvascular unist-related diseases

Published Papers (7 papers)

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Research

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23 pages, 3287 KiB

Open AccessArticle

Molecular Mechanisms and Therapeutic Implications of Human Pericyte-like Adipose-Derived Mesenchymal Stem Cells in an In Vitro Model of Diabetic Retinopathy

by Aleksandra Agafonova, Alessia Cosentino, Ivana Roberta Romano, Giovanni Giurdanella, Floriana D’Angeli, Rosario Giuffrida, Debora Lo Furno, Carmelina Daniela Anfuso, Giuliana Mannino and Gabriella Lupo

Int. J. Mol. Sci. 2024, 25(3), 1774; https://doi.org/10.3390/ijms25031774 - 01 Feb 2024

Cited by 1 | Viewed by 713

Abstract

The blood–retinal barrier (BRB) is strongly compromised in diabetic retinopathy (DR) due to the detachment of pericytes (PCs) from retinal microvessels, resulting in increased permeability and impairment of the BRB. Western blots, immunofluorescence and ELISA were performed on adipose mesenchymal stem cells (ASCs) and pericyte-like (P)-ASCs by co-cultured human retinal endothelial cells (HRECs) under hyperglycemic conditions (HG), as a model of DR. Our results demonstrated that: (a) platelet-derived growth factor receptor (PDGFR) and its activated form were more highly expressed in monocultured P-ASCs than in ASCs, and this expression increased when co-cultured with HRECs under high glucose conditions (HG); (b) the transcription factor Nrf2 was more expressed in the cytoplasmic fraction of ASCs and in the P-ASC nuclear fraction, under normal glucose and, even more, under HG conditions; (c) cytosolic phospholipase A₂ activity and prostaglandin E2 release, stimulated by HG, were significantly reduced in P-ASCs co-cultured with HRECs; (d) HO-1 protein content was significantly higher in HG-P-ASCs/HRECs than P-ASCs/HRECs; and (e) VEGF-A levels in media from HG-co-cultures were reduced in P-ASCs/HRECs with respect to ASCs/HRECs. The data obtained highlighted the potential of autologous differentiated ASCs in future clinical applications based on cell therapy to counteract the damage induced by DR. Full article

(This article belongs to the Special Issue Blood-Brain Barrier and Blood-Retinal Barrier Diseases: Molecular Mechanisms, Patterns, and New Concepts)

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17 pages, 3063 KiB

Open AccessArticle

The Expression of Major Facilitator Superfamily Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is Altered in the Retinas of a 5xFAD Mouse Model of Alzheimer’s Disease

by Irena Jovanovic Macura, Ana Zivanovic, Milka Perovic, Jelena Ciric, Tamara Major, Selma Kanazir and Sanja Ivkovic

Int. J. Mol. Sci. 2023, 24(18), 14092; https://doi.org/10.3390/ijms241814092 - 14 Sep 2023

Cited by 1 | Viewed by 1290

Abstract

Cerebral amyloid angiopathy (CAA) is characterized by amyloid β (Aβ) accumulation in the blood vessels and is associated with cognitive impairment in Alzheimer’s disease (AD). The increased accumulation of Aβ is also present in the retinal blood vessels and a significant correlation between retinal and brain amyloid deposition was demonstrated in living patients and animal AD models. The Aβ accumulation in the retinal blood vessels can be the result of impaired transcytosis and/or the dysfunctional ocular glymphatic system in AD and during aging. We analyzed the changes in the mRNA and protein expression of major facilitator superfamily domain-containing protein2a (Mfsd2a), the major regulator of transcytosis, and of Aquaporin4 (Aqp4), the key player implicated in the functioning of the glymphatic system, in the retinas of 4- and 12-month-old WT and 5xFAD female mice. A strong decrease in the Mfsd2a mRNA and protein expression was observed in the 4 M and 12 M 5xFAD and 12 M WT retinas. The increase in the expression of srebp1-c could be at least partially responsible for the Mfsd2a decrease in the 4 M 5xFAD retinas. The decrease in the pericyte (CD13+) coverage of retinal blood vessels in the 4 M and 12 M 5xFAD retinas and in the 12 M WT retinas suggests that pericyte loss could be associated with the Mfsd2a downregulation in these experimental groups. The observed increase in Aqp4 expression in 4 M and 12 M 5xFAD and 12 M WT retinas accompanied by the decreased perivascular Aqp4 expression is indicative of the impaired glymphatic system. The findings in this study reveal the impaired Mfsd2a and Aqp4 expression and Aqp4 perivascular mislocalization in retinal blood vessels during physiological (WT) and pathological (5xFAD) aging, indicating their importance as putative targets for the development of new treatments that can improve the regulation of transcytosis or the function of the glymphatic system. Full article

(This article belongs to the Special Issue Blood-Brain Barrier and Blood-Retinal Barrier Diseases: Molecular Mechanisms, Patterns, and New Concepts)

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14 pages, 3893 KiB

Open AccessArticle

Neuroinflammatory Dysfunction of the Blood–Brain Barrier and Basement Membrane Dysplasia Play a Role in the Development of Drug-Resistant Epilepsy

by Yulia Zabrodskaya, Natalia Paramonova, Anastasia Litovchenko, Elena Bazhanova, Aleksandr Gerasimov, Darya Sitovskaya, Victoria Nezdorovina, Svetlana Kravtsova, Stanislav Malyshev, Ekaterina Skiteva and Konstantin Samochernykh

Int. J. Mol. Sci. 2023, 24(16), 12689; https://doi.org/10.3390/ijms241612689 - 11 Aug 2023

Cited by 1 | Viewed by 1204

Abstract

Drug-resistance epilepsy (DRE) is a key problem in neurology. It is possible that damage to the blood–brain barrier (BBB) may affect resistance in DRE. The aim of this work was to assess the damage and dysfunction in the BBB in the area of epileptic foci in patients with DRE under conditions of neuroinflammation. The changes to the BBB in temporal lobe epilepsy (by immunohistochemistry and transmission electron microscopy), levels of neuroinflammatory proteins, and cytokine levels in the blood (by multiplex analysis) were studied. Increased levels of vascular endothelial growth factor (VEGF) and growth-regulated protein (GRO), and decreased levels of epidermal growth factor (EGF) in plasma, combined with overexpression of the VEGF-A receptor by endotheliocytes were detected. Malformation-like growths of the basement membrane of the capillaries of the brain complicate the delivery of antiepileptic drugs (AEDs). Dysplasia of the basement membrane is the result of inadequate reparative processes in chronic inflammation. In conclusion, it should be noted that damage to the microcirculatory network of the brain should be considered one of the leading factors contributing to DRE. Full article

(This article belongs to the Special Issue Blood-Brain Barrier and Blood-Retinal Barrier Diseases: Molecular Mechanisms, Patterns, and New Concepts)

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14 pages, 2910 KiB

Open AccessArticle

VEGF Induces Expression of Genes That Either Promote or Limit Relaxation of the Retinal Endothelial Barrier

by Maximilian McCann, Yueru Li, Basma Baccouche and Andrius Kazlauskas

Int. J. Mol. Sci. 2023, 24(7), 6402; https://doi.org/10.3390/ijms24076402 - 29 Mar 2023

Cited by 1 | Viewed by 1367

Abstract

The purpose of this study was to identify genes that mediate VEGF-induced permeability. We performed RNA-Seq analysis on primary human retinal endothelial cells (HRECs) cultured in normal (5 mM) and high glucose (30 mM) conditions that were treated with vehicle, VEGF, or VEGF then anti-VEGF. We filtered our RNA-Seq dataset to identify genes with the following four characteristics: (1) regulated by VEGF, (2) VEGF regulation reversed by anti-VEGF, (3) regulated by VEGF in both normal and high glucose conditions, and (4) known contribution to vascular homeostasis. Of the resultant 18 genes, members of the Notch signaling pathway and ANGPT2 (Ang2) were selected for further study. Permeability assays revealed that while the Notch pathway was dispensable for relaxing the barrier, it contributed to maintaining an open barrier. In contrast, Ang2 limited the extent of barrier relaxation in response to VEGF. These findings indicate that VEGF engages distinct sets of genes to induce and sustain barrier relaxation. Furthermore, VEGF induces expression of genes that limit the extent of barrier relaxation. Together, these observations begin to elucidate the elegance of VEGF-mediated transcriptional regulation of permeability. Full article

(This article belongs to the Special Issue Blood-Brain Barrier and Blood-Retinal Barrier Diseases: Molecular Mechanisms, Patterns, and New Concepts)

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28 pages, 4235 KiB

Open AccessArticle

Combined Micellar Liquid Chromatography Technique and QSARs Modeling in Predicting the Blood–Brain Barrier Permeation of Heterocyclic Drug-like Compounds

by Małgorzata Janicka, Anna Śliwińska, Małgorzata Sztanke and Krzysztof Sztanke

Int. J. Mol. Sci. 2022, 23(24), 15887; https://doi.org/10.3390/ijms232415887 - 14 Dec 2022

Cited by 3 | Viewed by 1200

Abstract

The quantitative structure–activity relationship (QSAR) methodology was used to predict the blood–brain permeability (log BB) for 65 synthetic heterocyclic compounds tested as promising drug candidates. The compounds were characterized by different descriptors: lipophilicity, parachor, polarizability, molecular weight, number of hydrogen bond acceptors, number of rotatable bonds, and polar surface area. Lipophilic properties of the compounds were evaluated experimentally by micellar liquid chromatography (MLC). In the experiments, sodium dodecyl sulfate (SDS) as the effluent component and the ODS-2 column were used. Using multiple linear regression and leave-one-out cross-validation, we derived the statistically significant and highly predictive quantitative structure–activity relationship models. Thus, this study provides valuable information on the expected properties of the substances that can be used as a support tool in the design of new therapeutic agents. Full article

(This article belongs to the Special Issue Blood-Brain Barrier and Blood-Retinal Barrier Diseases: Molecular Mechanisms, Patterns, and New Concepts)

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Review

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24 pages, 1322 KiB

Open AccessReview

Microglia and the Blood–Brain Barrier: An External Player in Acute and Chronic Neuroinflammatory Conditions

by Giorgia Serena Gullotta, Giuseppe Costantino, Maria Angela Sortino and Simona Federica Spampinato

Int. J. Mol. Sci. 2023, 24(11), 9144; https://doi.org/10.3390/ijms24119144 - 23 May 2023

Cited by 5 | Viewed by 4484

Abstract

Microglia are the resident immune cells of the central nervous system that guarantee immune surveillance and exert also a modulating role on neuronal synaptic development and function. Upon injury, microglia get activated and modify their morphology acquiring an ameboid phenotype and pro- or anti-inflammatory features. The active role of microglia in blood–brain barrier (BBB) function and their interaction with different cellular components of the BBB—endothelial cells, astrocytes and pericytes—are described. Here, we report the specific crosstalk of microglia with all the BBB cell types focusing in particular on the involvement of microglia in the modulation of BBB function in neuroinflammatory conditions that occur in conjunction with an acute event, such as a stroke, or in a slow neurodegenerative disease, such as Alzheimer’s disease. The potential of microglia to exert a dual role, either protective or detrimental, depending on disease stages and environmental conditioning factors is also discussed. Full article

(This article belongs to the Special Issue Blood-Brain Barrier and Blood-Retinal Barrier Diseases: Molecular Mechanisms, Patterns, and New Concepts)

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40 pages, 2598 KiB

Open AccessReview

Retinitis Pigmentosa: Current Clinical Management and Emerging Therapies

by Xuan-Thanh-An Nguyen, Lude Moekotte, Astrid S. Plomp, Arthur A. Bergen, Maria M. van Genderen and Camiel J. F. Boon

Int. J. Mol. Sci. 2023, 24(8), 7481; https://doi.org/10.3390/ijms24087481 - 19 Apr 2023

Cited by 7 | Viewed by 5806

Abstract

Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies characterized by the degeneration of rod photoreceptors, followed by the degeneration of cone photoreceptors. As a result of photoreceptor degeneration, affected individuals experience gradual loss of visual function, with primary symptoms of progressive nyctalopia, constricted visual fields and, ultimately, central vision loss. The onset, severity and clinical course of RP shows great variability and unpredictability, with most patients already experiencing some degree of visual disability in childhood. While RP is currently untreatable for the majority of patients, significant efforts have been made in the development of genetic therapies, which offer new hope for treatment for patients affected by inherited retinal dystrophies. In this exciting era of emerging gene therapies, it remains imperative to continue supporting patients with RP using all available options to manage their condition. Patients with RP experience a wide variety of physical, mental and social-emotional difficulties during their lifetime, of which some require timely intervention. This review aims to familiarize readers with clinical management options that are currently available for patients with RP. Full article

(This article belongs to the Special Issue Blood-Brain Barrier and Blood-Retinal Barrier Diseases: Molecular Mechanisms, Patterns, and New Concepts)

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