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Article ; Online: Central Nervous System Pericytes Contribute to Health and Disease.

Girolamo, Francesco / Errede, Mariella / Bizzoca, Antonella / Virgintino, Daniela / Ribatti, Domenico

2022 Volume 11, Issue 10

Abstract: Successful neuroprotection is only possible with contemporary microvascular protection. The prevention of disease-induced vascular modifications that accelerate brain damage remains largely elusive. An improved understanding of pericyte (PC) signalling ... ...

Abstract	Successful neuroprotection is only possible with contemporary microvascular protection. The prevention of disease-induced vascular modifications that accelerate brain damage remains largely elusive. An improved understanding of pericyte (PC) signalling could provide important insight into the function of the neurovascular unit (NVU), and into the injury-provoked responses that modify cell-cell interactions and crosstalk. Due to sharing the same basement membrane with endothelial cells, PCs have a crucial role in the control of endothelial, astrocyte, and oligodendrocyte precursor functions and hence blood-brain barrier stability. Both cerebrovascular and neurodegenerative diseases impair oxygen delivery and functionally impair the NVU. In this review, the role of PCs in central nervous system health and disease is discussed, considering their origin, multipotency, functions and also dysfunction, focusing on new possible avenues to modulate neuroprotection. Dysfunctional PC signalling could also be considered as a potential biomarker of NVU pathology, allowing us to individualize therapeutic interventions, monitor responses, or predict outcomes.
MeSH term(s)	Astrocytes ; Blood-Brain Barrier/pathology ; Cell Communication ; Endothelial Cells/physiology ; Pericytes/pathology
Language	English
Publishing date	2022-05-20
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11101707
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Inter-Alpha Inhibitor Proteins Modify the Microvasculature after Exposure to Hypoxia-Ischemia and Hypoxia in Neonatal Rats.

Girolamo, Francesco / Lim, Yow-Pin / Virgintino, Daniela / Stonestreet, Barbara S / Chen, Xiaodi F

International journal of molecular sciences

2023 Volume 24, Issue 7

Abstract: Microvasculature develops during early brain development. Hypoxia-ischemia (HI) and hypoxia (H) predispose to brain injury in neonates. Inter-alpha inhibitor proteins (IAIPs) attenuate injury to the neonatal brain after exposure to HI. However, the ... ...

Abstract	Microvasculature develops during early brain development. Hypoxia-ischemia (HI) and hypoxia (H) predispose to brain injury in neonates. Inter-alpha inhibitor proteins (IAIPs) attenuate injury to the neonatal brain after exposure to HI. However, the effects of IAIPs on the brain microvasculature after exposure to HI have not been examined in neonates. Postnatal day-7 rats were exposed to sham treatment or right carotid artery ligation and 8% oxygen for 90 min. HI comprises hypoxia (H) and ischemia to the right hemisphere (HI-right) and hypoxia to the whole body, including the left hemisphere (H-left). Human IAIPs (hIAIPs, 30 mg/kg) or placebo were injected immediately, 24 and 48 h after HI/H. The brains were analyzed 72 h after HI/H to determine the effects of hIAIPs on the microvasculature by laminin immunohistochemistry and calculation of (1) the percentage area stained by laminin, (2) cumulative microvessel length, and (3) density of tunneling nanotubes (TNTs), which are sensitive indicators of the earliest phases of neo-vascularization/collateralization. hIAIPs mainly affected the percent of the laminin-stained area after HI/H, cumulative vessel length after H but not HI, and TNT density in females but not males. hIAIPs modify the effects of HI/H on the microvasculature after brain injury in neonatal rats and exhibit sex-related differential effects. Our findings suggest that treatment with hIAIPs after exposure to H and HI in neonatal rats affects the laminin content of the vessel basal lamina and angiogenic responses in a sex-related fashion.
MeSH term(s)	Female ; Rats ; Animals ; Humans ; Animals, Newborn ; Hypoxia-Ischemia, Brain/metabolism ; Laminin/metabolism ; Hypoxia/metabolism ; Brain/metabolism ; Ischemia ; Brain Injuries ; Microvessels/metabolism
Chemical Substances	Tunneling Nanotubes ; Laminin
Language	English
Publishing date	2023-04-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24076743
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Article ; Online: Central Nervous System Pericytes Contribute to Health and Disease

Francesco Girolamo / Mariella Errede / Antonella Bizzoca / Daniela Virgintino / Domenico Ribatti

Cells, Vol 11, Iss 1707, p

2022 Volume 1707

Abstract	Successful neuroprotection is only possible with contemporary microvascular protection. The prevention of disease-induced vascular modifications that accelerate brain damage remains largely elusive. An improved understanding of pericyte (PC) signalling could provide important insight into the function of the neurovascular unit (NVU), and into the injury-provoked responses that modify cell–cell interactions and crosstalk. Due to sharing the same basement membrane with endothelial cells, PCs have a crucial role in the control of endothelial, astrocyte, and oligodendrocyte precursor functions and hence blood–brain barrier stability. Both cerebrovascular and neurodegenerative diseases impair oxygen delivery and functionally impair the NVU. In this review, the role of PCs in central nervous system health and disease is discussed, considering their origin, multipotency, functions and also dysfunction, focusing on new possible avenues to modulate neuroprotection. Dysfunctional PC signalling could also be considered as a potential biomarker of NVU pathology, allowing us to individualize therapeutic interventions, monitor responses, or predict outcomes.
Keywords	Alzheimer’s disease ; angiogenesis ; mesoangioblast ; neurodevelopmental disorders ; neuroinflammation ; neurovascular unit ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Inter-Alpha Inhibitor Proteins Modify the Microvasculature after Exposure to Hypoxia–Ischemia and Hypoxia in Neonatal Rats

Francesco Girolamo / Yow-Pin Lim / Daniela Virgintino / Barbara S. Stonestreet / Xiaodi F. Chen

International Journal of Molecular Sciences, Vol 24, Iss 6743, p

2023 Volume 6743

Abstract: Microvasculature develops during early brain development. Hypoxia–ischemia (HI) and hypoxia (H) predispose to brain injury in neonates. Inter-alpha inhibitor proteins (IAIPs) attenuate injury to the neonatal brain after exposure to HI. However, the ... ...

Abstract	Microvasculature develops during early brain development. Hypoxia–ischemia (HI) and hypoxia (H) predispose to brain injury in neonates. Inter-alpha inhibitor proteins (IAIPs) attenuate injury to the neonatal brain after exposure to HI. However, the effects of IAIPs on the brain microvasculature after exposure to HI have not been examined in neonates. Postnatal day-7 rats were exposed to sham treatment or right carotid artery ligation and 8% oxygen for 90 min. HI comprises hypoxia (H) and ischemia to the right hemisphere (HI-right) and hypoxia to the whole body, including the left hemisphere (H-left). Human IAIPs (hIAIPs, 30 mg/kg) or placebo were injected immediately, 24 and 48 h after HI/H. The brains were analyzed 72 h after HI/H to determine the effects of hIAIPs on the microvasculature by laminin immunohistochemistry and calculation of (1) the percentage area stained by laminin, (2) cumulative microvessel length, and (3) density of tunneling nanotubes (TNTs), which are sensitive indicators of the earliest phases of neo-vascularization/collateralization. hIAIPs mainly affected the percent of the laminin-stained area after HI/H, cumulative vessel length after H but not HI, and TNT density in females but not males. hIAIPs modify the effects of HI/H on the microvasculature after brain injury in neonatal rats and exhibit sex-related differential effects. Our findings suggest that treatment with hIAIPs after exposure to H and HI in neonatal rats affects the laminin content of the vessel basal lamina and angiogenic responses in a sex-related fashion.
Keywords	blood–brain barrier ; hypoxia–ischemia ; inter-alpha inhibitor proteins ; laminin ; tunneling nanotubes ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Time Course of Changes in the Neurovascular Unit after Hypoxic-Ischemic Injury in Neonatal Rats.

Hatayama, Kazuki / Riddick, Sydney / Awa, Fares / Chen, Xiaodi / Virgintino, Daniela / Stonestreet, Barbara S

International journal of molecular sciences

2022 Volume 23, Issue 8

Abstract: Exposure to hypoxic-ischemic (HI) insults in newborns can predispose them to severe neurological sequela. The mechanisms underlying HI-related brain injury have not been completely elucidated. The neurovascular unit (NVU) is a composite of structures ... ...

Abstract	Exposure to hypoxic-ischemic (HI) insults in newborns can predispose them to severe neurological sequela. The mechanisms underlying HI-related brain injury have not been completely elucidated. The neurovascular unit (NVU) is a composite of structures that protect the brain from the influx of detrimental molecules. Changes in the NVU after HI are important because they could reveal endogenous neuroprotective pathways in the cerebral microvasculature. Furthermore, the time course of changes in the NVU after exposure to HI in the newborn remains to be determined. In this study, we examined the effects of severe HI on the time course of changes in the NVU in neonatal rats. Brains were collected from rats exposed to right carotid artery ligation and 2 h of hypoxia on postnatal day 7 with recovery for 6 or 48 h after exposure to sham treatment (Sham) or HI. The right HI and left hypoxic alone sides of the brains were examined by quantitative immunohistochemistry for vascular density (laminin), pericyte vascular coverage (PDGFRβ), astrocyte vascular coverage (GFAP), and claudin-5 expression in the microvasculature of the cerebral cortex, white matter, and hippocampus. HI-related brain injury in neonatal rats was associated with increases in vascular density in the cortex and hippocampus 48 h after HI as well as neurovascular remodeling, including loss of pericyte coverage in the cortex and increases in claudin-5 in the hippocampus 6 h after HI. Astrocyte coverage was not affected by HI injury. The time course of the responses in the different components of the NVU varied after exposure to HI. There were also differential regional responses in the elements of the NVU in response to HI and hypoxia alone.
MeSH term(s)	Animals ; Animals, Newborn ; Brain/metabolism ; Brain Injuries/metabolism ; Claudin-5/metabolism ; Hypoxia/metabolism ; Hypoxia-Ischemia, Brain/metabolism ; Ischemia/metabolism ; Rats
Chemical Substances	Claudin-5
Language	English
Publishing date	2022-04-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23084180
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: High-Resolution Confocal Imaging of Pericytes in Human Fetal Brain Microvessels.

Errede, Mariella / Girolamo, Francesco / Virgintino, Daniela

Methods in molecular biology (Clifton, N.J.)

2019 Volume 2206, Page(s) 143–150

Abstract: Pericytes are integral part of neurovascular unit and play a role in the maintenance of blood-brain barrier integrity, angiogenesis, and cerebral blood flow regulation. Despite their important functional roles, a univocal phenotypic identification is ... ...

Abstract	Pericytes are integral part of neurovascular unit and play a role in the maintenance of blood-brain barrier integrity, angiogenesis, and cerebral blood flow regulation. Despite their important functional roles, a univocal phenotypic identification is still emerging also for the lack of a "pan-pericyte" marker. In the present study, we describe in detail the method for performing fluorescence immunohistochemistry on thick free-floating sections from human fetal brain in high resolution laser confocal microscopy. This method enables to obtain three-dimensional images of pericytes and provides insights about their distribution and localization in the microvessels of human developing brain.
MeSH term(s)	Blood-Brain Barrier/cytology ; Brain/blood supply ; Cerebrovascular Circulation/physiology ; Humans ; Imaging, Three-Dimensional/methods ; Immunohistochemistry/methods ; Microscopy, Confocal/methods ; Microvessels/cytology ; Neovascularization, Physiologic/physiology ; Pericytes/cytology
Language	English
Publishing date	2019-05-09
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-0916-3_11
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Article ; Online: Neural crest cell-derived pericytes act as pro-angiogenic cells in human neocortex development and gliomas.

Girolamo, Francesco / de Trizio, Ignazio / Errede, Mariella / Longo, Giovanna / d'Amati, Antonio / Virgintino, Daniela

Fluids and barriers of the CNS

2021 Volume 18, Issue 1, Page(s) 14

Abstract: Central nervous system diseases involving the parenchymal microvessels are frequently associated with a 'microvasculopathy', which includes different levels of neurovascular unit (NVU) dysfunction, including blood-brain barrier alterations. To contribute ...

Abstract	Central nervous system diseases involving the parenchymal microvessels are frequently associated with a 'microvasculopathy', which includes different levels of neurovascular unit (NVU) dysfunction, including blood-brain barrier alterations. To contribute to the understanding of NVU responses to pathological noxae, we have focused on one of its cellular components, the microvascular pericytes, highlighting unique features of brain pericytes with the aid of the analyses carried out during vascularization of human developing neocortex and in human gliomas. Thanks to their position, centred within the endothelial/glial partition of the vessel basal lamina and therefore inserted between endothelial cells and the perivascular and vessel-associated components (astrocytes, oligodendrocyte precursor cells (OPCs)/NG2-glia, microglia, macrophages, nerve terminals), pericytes fulfil a central role within the microvessel NVU. Indeed, at this critical site, pericytes have a number of direct and extracellular matrix molecule- and soluble factor-mediated functions, displaying marked phenotypical and functional heterogeneity and carrying out multitasking services. This pericytes heterogeneity is primarily linked to their position in specific tissue and organ microenvironments and, most importantly, to their ontogeny. During ontogenesis, pericyte subtypes belong to two main embryonic germ layers, mesoderm and (neuro)ectoderm, and are therefore expected to be found in organs ontogenetically different, nonetheless, pericytes of different origin may converge and colonize neighbouring areas of the same organ/apparatus. Here, we provide a brief overview of the unusual roles played by forebrain pericytes in the processes of angiogenesis and barriergenesis by virtue of their origin from midbrain neural crest stem cells. A better knowledge of the ontogenetic subpopulations may support the understanding of specific interactions and mechanisms involved in pericyte function/dysfunction, including normal and pathological angiogenesis, thereby offering an alternative perspective on cell subtype-specific therapeutic approaches.
MeSH term(s)	Glioma/physiopathology ; Humans ; Neocortex/blood supply ; Neocortex/growth & development ; Neovascularization, Pathologic/physiopathology ; Neovascularization, Physiologic/physiology ; Neural Crest/cytology ; Pericytes/physiology
Language	English
Publishing date	2021-03-20
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2595406-4
ISSN	2045-8118 ; 2045-8118
ISSN (online)	2045-8118
ISSN	2045-8118
DOI	10.1186/s12987-021-00242-7
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Article: Autophagy increase in Merosin-Deficient Congenital Muscular Dystrophy type 1A.

Mastrapasqua, Mariangela / Rossi, Roberta / De Cosmo, Lucrezia / Resta, Annalisa / Errede, Mariella / Bizzoca, Antonella / Zampatti, Stefania / Resta, Nicoletta / Giardina, Emiliano / Ruggieri, Maddalena / Virgintino, Daniela / Annese, Tiziana / Laforgia, Nicola / Girolamo, Francesco

European journal of translational myology

2023 Volume 33, Issue 3

Abstract: The autophagy process recycles dysfunctional cellular components and protein aggregates by sequestering them in autophagosomes directed to lysosomes for enzymatic degradation. A basal level of autophagy is essential for skeletal muscle maintenance. ... ...

Abstract	The autophagy process recycles dysfunctional cellular components and protein aggregates by sequestering them in autophagosomes directed to lysosomes for enzymatic degradation. A basal level of autophagy is essential for skeletal muscle maintenance. Increased autophagy occurs in several forms of muscular dystrophy and in the merosin-deficient congenital muscular dystrophy 1A mouse model (dy3k/dy3k) lacking the laminin-α2 chain. This pilot study aimed to compare autophagy marker expression and autophagosomes presence using light and electron microscopes and western blotting in diagnostic muscle biopsies from newborns affected by different congenital muscular myopathies and dystrophies. Morphological examination showed dystrophic muscle features, predominance of type 2A myofibers, accumulation of autophagosomes in the subsarcolemmal areas, increased number of autophagosomes overexpressing LC3b, Beclin-1 and ATG5, in the merosin-deficient newborn suggesting an increased autophagy. In Duchenne muscular dystrophy, nemaline myopathy, and spinal muscular atrophy the predominant accumulation of p62+ puncta rather suggests an autophagy impairment.
Language	English
Publishing date	2023-07-28
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2545577-1
ISSN	2037-7460 ; 2037-7452
ISSN (online)	2037-7460
ISSN	2037-7452
DOI	10.4081/ejtm.2023.11501
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Article ; Online: Enteric Glia and Brain Astroglia: Complex Communication in Health and Disease along the Gut-Brain Axis.

D'Antongiovanni, Vanessa / Pellegrini, Carolina / Antonioli, Luca / Ippolito, Chiara / Segnani, Cristina / Benvenuti, Laura / D'Amati, Antonio / Errede, Mariella / Virgintino, Daniela / Fornai, Matteo / Bernardini, Nunzia

The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry

2023 , Page(s) 10738584231163460

Abstract: Several studies have provided interesting evidence about the role of the bidirectional communication between the gut and brain in the onset and development of several pathologic conditions, including inflammatory bowel diseases (IBDs), neurodegenerative ... ...

Abstract	Several studies have provided interesting evidence about the role of the bidirectional communication between the gut and brain in the onset and development of several pathologic conditions, including inflammatory bowel diseases (IBDs), neurodegenerative diseases, and related comorbidities. Indeed, patients with IBD can experience neurologic disorders, including depression and cognitive impairment, besides typical intestinal symptoms. In parallel, patients with neurodegenerative disease, such as Parkinson disease and Alzheimer disease, are often characterized by the occurrence of functional gastrointestinal disorders. In this context, enteric glial cells and brain astrocytes are emerging as pivotal players in the initiation/maintenance of neuroinflammatory responses, which appear to contribute to the alterations of intestinal and neurologic functions observed in patients with IBD and neurodegenerative disorders. The present review was conceived to provide a comprehensive and critical overview of the available knowledge on the morphologic, molecular, and functional changes occurring in the enteric glia and brain astroglia in IBDs and neurologic disorders. In addition, our intent is to identify whether such alterations could represent a common denominator involved in the onset of comorbidities associated with the aforementioned disorders. This might help to identify putative targets useful to develop novel pharmacologic approaches for the therapeutic management of such disturbances.
Language	English
Publishing date	2023-04-13
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1233753-5
ISSN	1089-4098 ; 1073-8584
ISSN (online)	1089-4098
ISSN	1073-8584
DOI	10.1177/10738584231163460
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Zs.A 4315: Show issues

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Article ; Online: Expression of P-gp in Glioblastoma: What we can Learn from Brain Development.

de Trizio, Ignazio / Errede, Mariella / d'Amati, Antonio / Girolamo, Francesco / Virgintino, Daniela

Current pharmaceutical design

2020 Volume 26, Issue 13, Page(s) 1428–1437

Abstract: P-Glycoprotein (P-gp) is a 170-kDa transmembrane glycoprotein that works as an efflux pump and confers multidrug resistance (MDR) in normal tissues and tumors, including nervous tissues and brain tumors. In the developing telencephalon, the endothelial ... ...

Abstract	P-Glycoprotein (P-gp) is a 170-kDa transmembrane glycoprotein that works as an efflux pump and confers multidrug resistance (MDR) in normal tissues and tumors, including nervous tissues and brain tumors. In the developing telencephalon, the endothelial expression of P-gp, and the subcellular localization of the transporter at the luminal endothelial cell (EC) plasma membrane are early hallmarks of blood-brain barrier (BBB) differentiation and suggest a functional BBB activity that may complement the placental barrier function and the expression of P-gp at the blood-placental interface. In early fetal ages, P-gp has also been immunolocalized on radial glia cells (RGCs), located in the proliferative ventricular zone (VZ) of the dorsal telencephalon and now considered to be neural progenitor cells (NPCs). RG-like NPCs have been found in many regions of the developing brain and have been suggested to give rise to neural stem cells (NSCs) of adult subventricular (SVZ) neurogenic niches. The P-gp immunosignal, associated with RG-like NPCs during cortical histogenesis, progressively decreases in parallel with the last waves of neuroblast migrations, while 'outer' RGCs and the deriving astrocytes do not stain for the efflux transporter. These data suggest that in human glioblastoma (GBM), P-gp expressed by ECs may be a negligible component of tumor MDR. Instead, tumor perivascular astrocytes may dedifferentiate and resume a progenitor-like P-gp activity, becoming MDR cells and contribute, together with perivascular P-gpexpressing glioma stem-like cells (GSCs), to the MDR profile of GBM vessels. In conclusion, the analysis of Pgp immunolocalization during brain development may contribute to identify the multiple cellular sources in the GBM vessels that may be involved in P-gp-mediated chemoresistance and can be responsible for GBM therapy failure and tumor recurrence.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; Adult ; Blood-Brain Barrier ; Brain/physiology ; Female ; Glioblastoma/drug therapy ; Humans ; Neoplasm Recurrence, Local ; Pregnancy
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B
Language	English
Publishing date	2020-03-30
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	1304236-1
ISSN	1873-4286 ; 1381-6128
ISSN (online)	1873-4286
ISSN	1381-6128
DOI	10.2174/1381612826666200318130625
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