Astrocytic neogenin/netrin-1 pathway promotes blood vessel homeostasis and function in mouse cortex

Yao, Lingling; Hu, Jinxia; Li, Qiang; Lee, Daehoon; Ren, Xiao; Zhang, Junshi; Sun, Dong; Zhang, Hongsheng; Wang, Yonggang; Mei, Lin; Xiong, Wen-Cheng

doi:10.1172/jci132372

Cited by 28 publications

(30 citation statements)

References 61 publications

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“…Our study supports the role of netrin-1 as a universal barrier stabilizer. This extends findings from previous studies: netrin-1 seals endothelial barriers like the blood–retina barrier in diabetic retinopathy [ 4 ] as well as the BBB in stroke [ 33 , 34 ], hemorrhage [ 35 ], and experimental autoimmune encephalomyelitis [ 3 ]. However, the effects on barriers are more complex.…”

Section: Discussionsupporting

confidence: 88%

Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury

Chen

Schmidt

Schürger

et al. 2021

IJMS

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The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain.

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Section: Discussionsupporting

confidence: 88%

Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury

Chen

Schmidt

Schürger

et al. 2021

IJMS

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“…Nevertheless, high levels of neogenin have been noticed in diffuse intrinsic pontine gliomas, affecting tumor invasion [65]. Its deficiency was also associated with the Moyamoya-like vasculopathy [66], and its depletion in mouse brains was correlated with abnormally permeable blood vessels with a reduced blood flow, disrupted vascular basement membranes, a declined number of pericytes, compromised BEC barrier, and increased BEC proliferation [67]. It is possible that miR-18a influences neogenin expression in BAVMs, however, to the best of our knowledge, this has yet to be investigated.…”

Section: Mir-18amentioning

confidence: 99%

An Insight into the microRNAs Associated with Arteriovenous and Cavernous Malformations of the Brain

Florian

Buruiană

Şuşman

et al. 2021

Cells

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Background: Brain arteriovenous malformations (BAVMs) and cerebral cavernous malformations (CCMs) are rare developmental anomalies of the intracranial vasculature, with an irregular tendency to rupture, and as of yet incompletely deciphered pathophysiology. Because of their variety in location, morphology, and size, as well as unpredictable natural history, they represent a management challenge. MicroRNAs (miRNAs) are strands of non-coding RNA of around 20 nucleotides that are able to modulate the expression of target genes by binding completely or partially to their respective complementary sequences. Recent breakthroughs have been made on elucidating their contribution to BAVM and CCM occurrence, growth, and evolution; however, there are still countless gaps in our understanding of the mechanisms involved. Methods: We have searched the Medline (PubMed; PubMed Central) database for pertinent articles on miRNAs and their putative implications in BAVMs and CCMs. To this purpose, we employed various permutations of the terms and idioms: ‘arteriovenous malformation’, ‘AVM’, and ‘BAVM’, or ‘cavernous malformation’, ‘cavernoma’, and ‘cavernous angioma’ on the one hand; and ‘microRNA’, ‘miRNA’, and ‘miR’ on the other. Using cross-reference search; we then investigated additional articles concerning the individual miRNAs identified in other cerebral diseases. Results: Seven miRNAs were discovered to play a role in BAVMs, three of which were downregulated (miR-18a, miR-137, and miR-195*) and four upregulated (miR-7-5p, miR-199a-5p, miR-200b-3p, and let-7b-3p). Similarly, eight miRNAs were identified in CCM in humans and experimental animal models, two being upregulated (miR-27a and mmu-miR-3472a), and six downregulated (miR-125a, miR-361-5p, miR-370-3p, miR-181a-2-3p, miR-95-3p, and let-7b-3p). Conclusions: The following literature review endeavored to address the recent discoveries related to the various implications of miRNAs in the formation and growth of BAVMs and CCMs. Additionally, by presenting other cerebral pathologies correlated with these miRNAs, it aimed to emphasize the potential directions of upcoming research and biological therapies.

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“…Single cell RNA sequencing studies indicate that Netrin1 is highly expressed in adult brain pericytes, indicating that pericytes are a likely source of Netrin1 production and Unc5B activation at the BBB 34 . Interestingly, Netrin1 was shown to be implicated in BBB integrity, upregulated in brain ECs in response to brain injury, and to increase Claudin5 expression 35,36 , therefore multiple cellular sources and environmental modulations of Netrin1 expression could contribute to BBB integrity. Since we could target Unc5B via i.v.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Unc5B controls blood-brain barrier integrity

Boyé

Geraldo

Furtado

et al. 2021

Preprint

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Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). Here, we showed that the endothelial Netrin1 receptor Unc5B controls BBB integrity by maintaining Wnt/β-catenin signaling. Inducible endothelial-specific deletion of Unc5B in adult mice led to region and size-selective BBB opening. Loss of Unc5B decreased BBB Wnt/β-catenin signaling, and β-catenin overexpression rescued Unc5B mutant BBB defects. Mechanistically, Netrin1 enhanced Unc5B interaction with the Wnt co-receptor LRP6, induced its phosphorylation and activated Wnt/β-catenin downstream signaling. Intravenous delivery of antibodies blocking Netrin1 binding to Unc5B caused a transient disruption of Wnt signaling and BBB breakdown, followed by neurovascular barrier resealing. These data identify Netrin-Unc5B signaling as a novel regulator of BBB integrity with potential therapeutic utility for CNS diseases.

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Astrocytic neogenin/netrin-1 pathway promotes blood vessel homeostasis and function in mouse cortex

Cited by 28 publications

References 61 publications

Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury

Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury

An Insight into the microRNAs Associated with Arteriovenous and Cavernous Malformations of the Brain

Endothelial Unc5B controls blood-brain barrier integrity

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