In utero alcohol exposure exacerbates endothelial protease activity from pial microvessels and impairs GABA interneuron positioning

Léger, Cécile; Dupré, Nicolas; Laquerrière, Annie; Lecointre, Maryline; Dumanoir, Marion; Janin, François; Hauchecorne, M.; Fabre, Maëlle; Jégou, Sylvie; Frébourg, Thierry; Cléren, Carine; Leroux, Philippe; Marcorelles, Pascale; Brasse‐Lagnel, Carole; Marret, Stéphane; Marguet, Florent; Gonzalez, Bruno J.

doi:10.1016/j.nbd.2020.105074

Cited by 10 publications

(14 citation statements)

References 57 publications

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“…Furthermore, these authors provided for the first time mechanistic and functional evidence that upon in utero exposure, alcohol impairs glutamate-regulated activity of pial microvessels and IN positioning by altering metalloproteinase activity. From these results, it could be suggested that alcohol-induced endothelial dysfunction may contribute to ectopic cortical GABAergic IN positioning observed in the present FASD cases [31].…”

Section: Discussionsupporting

confidence: 52%

Prenatal alcohol exposure is a leading cause of interneuronopathy in humans

Marguet

Friocourt

Brosolo

et al. 2020

acta neuropathol commun

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Alcohol affects multiple neurotransmitter systems, notably the GABAergic system and has been recognised for a long time as particularly damaging during critical stages of brain development. Nevertheless, data from the literature are most often derived from animal or in vitro models. In order to study the production, migration and cortical density disturbances of GABAergic interneurons upon prenatal alcohol exposure, we performed immunohistochemical studies by means of the proliferation marker Ki67, GABA and calretinin antibodies in the frontal cortical plate of 17 foetal and infant brains antenatally exposed to alcohol, aged 15 weeks’ gestation to 22 postnatal months and in the ganglionic eminences and the subventricular zone of the dorsal telencephalon until their regression, i.e., 34 weeks’ gestation. Results were compared with those obtained in 17 control brains aged 14 weeks of gestation to 35 postnatal months. We also focused on interneuron vascular migration along the cortical microvessels by confocal microscopy with double immunolabellings using Glut1, GABA and calretinin. Semi-quantitative and quantitative analyses of GABAergic and calretininergic interneuron density allowed us to identify an insufficient and delayed production of GABAergic interneurons in the ganglionic eminences during the two first trimesters of the pregnancy and a delayed incorporation into the laminar structures of the frontal cortex. Moreover, a mispositioning of GABAergic and calretininergic interneurons persisted throughout the foetal life, these cells being located in the deep layers instead of the superficial layers II and III. Moreover, vascular migration of calretininergic interneurons within the cortical plate was impaired, as reflected by low numbers of interneurons observed close to the cortical perforating vessel walls that may in part explain their abnormal intracortical distribution. Our results are globally concordant with those previously obtained in mouse models, in which alcohol has been shown to induce an interneuronopathy by affecting interneuron density and positioning within the cortical plate, and which could account for the neurological disabilities observed in children with foetal alcohol disorder spectrum.

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Section: Discussionsupporting

confidence: 52%

Prenatal alcohol exposure is a leading cause of interneuronopathy in humans

Marguet

Friocourt

Brosolo

et al. 2020

acta neuropathol commun

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“…For example, in a cohort of Swedish children with FAS, fundus analysis revealed tortuosity of large vessels and optic nerve hypoplasia with deleterious consequences to the visual function of children ( Strömland, 1982 ; Pinazo-Duran et al, 1997 ; Hellström, 1999 ). However, to our knowledge, retinal angiogenic and neurovascular defects similar to those observed in the developing neocortex have not been reported in the literature ( Léger et al, 2020b ; Marguet et al, 2020 ).…”

Section: Introductionmentioning

confidence: 78%

“…Since some GABAergic interneuron subpopulations migrate along radial microvessels in the developing neocortex ( Léger et al, 2020a , b ; Won et al, 2013 ), we explored whether such neurovascular interactions exist in the developing retina. Double immunolabeling experiments targeting calretinin and microvessels were performed at P15 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, two nervous cell types, GABAergic interneurons ( Won et al, 2013 ) and oligodendrocytes ( Tsai et al, 2016 ), require vessels as guides during their migration. Recent data from our research group showed a disruption of the vessel-associated migration of GABAergic interneurons ( Léger et al, 2020a , b ; Marguet et al, 2020 ). Nevertheless, even if intracortical microvasculature disorganisation resulting from in utero alcohol exposure could be a promising tool for the early diagnosis of FASD, access to brain microvessels by means of MRI remains challenging in human neonates.…”

Section: Introductionmentioning

confidence: 91%

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In UteroAlcohol Exposure Impairs Retinal Angiogenesis and the Microvessel-Associated Positioning of Calretinin Interneurons

Dumanoir

Leroy

Burel

et al. 2023

eNeuro

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In addition to brain disorders, which constitute a devastating consequence of prenatal alcohol exposure (PAE), eye development is also significantly affected. Given that the retina is a readily accessible part of the central nervous system, a better understanding of the impact of ethanol on retinal development might provide ophthalmological landmarks helpful for early diagnosis of foetal alcohol syndrome. This study aimed to provide a fine morphometric and cellular characterization of the development of retinal microvasculature and neurovascular interactions in a mouse model of foetal alcohol spectrum disorder. The data revealed that PAE impaired superficial vascular plexus development. In particular, progression of the vascular migration front was significantly decreased in PAE retinas, supporting a delay in plexus progression. Moreover, a significant decrease in the vessel density and number of perforating vessels was quantified in PAE mice, supporting less angiogenesis. The present study provides also the first evidence of a close interaction between migrating calretinin-positive interneurons and perforating microvessels in the inner nuclear layer of the developing retina. This neurovascular association was significantly impaired by PAE. Moreover, projections of amacrine cells were abnormally distributed and densified in stratum S1 and S2. In humans, comparison of a 5-month-old control infant with a 3-month-old alcohol-exposed case revealed a similar mispositioning of calretinin-positive interneurons. This opens new research avenues regarding a neurovascular contribution in the deleterious effects of alcohol in the developing retina and support that ophthalmological examination could become a promising approach for early detection of alcohol-exposed infants presenting with neurovascular brain defects.Significance StatementIn the developing brain, prenatal alcohol exposure (PAE) has been shown to disorganize cortical vasculature leading to defective layering of interneurons which use radial microvessels to enter the neocortex. Using a murine model of FASD, here we show that PAE impairs the retinal microvasculature development and neuronal organization. In particular, migrating calretinin-positive interneurons of the internal nuclear layer are associated with perforating microvessels. PAE reduces the number of vessel-associated calretininergic cells and impairs their positioning. The mispositioning of calretinin-positive interneurons is also observed in a human FAS infant. These findings provide new evidence that PAE-induced cortical impairments are found in retina. They offer promising tools for the early diagnosis of brain impairments in infants in utero exposed to alcohol.

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“…Recent studies also support the hypothesis that alcohol exposure impairs both the osteogenic differentiation of BMSCs and the process of neovascularization. 26 , 27 However, the inhibiting effect of alcohol on the bone healing process, particularly on bone formation and neovascularization, remains insufficiently understood.…”

Section: Introductionmentioning

confidence: 99%

Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axis

Zhu

Fang

et al. 2022

Bone & Joint Research

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Aims Alcoholism is a well-known detrimental factor in fracture healing. However, the underlying mechanism of alcohol-inhibited fracture healing remains poorly understood. Methods MicroRNA (miR) sequencing was performed on bone mesenchymal stem cells (BMSCs). The effects of alcohol and miR-19a-3p on vascularization and osteogenic differentiation were analyzed in vitro using BMSCs and human umbilical vein endothelial cells (HUVECs). An in vivo alcohol-fed mouse model of femur fracture healing was also established, and radiological and histomorphometric analyses were used to evaluate the role of miR-19a-3p. The binding of miR-19a-3p to forkhead box F2 (FOXF2) was analyzed using a luciferase reporter assay. Results miR-19a-3p was identified as one of the key regulators in the osteogenic differentiation of BMSCs, and was found to be downregulated in the alcohol-fed mouse model of fracture healing. In vitro, miR-19a-3p expression was downregulated after ethanol administration in both BMSCs and HUVECs. Vascularization and osteogenic differentiation were independently suppressed by ethanol and reversed by miR-19a-3p. In addition, the luciferase reporter assay showed that FOXF2 is the direct binding target of miR-19a-3p. In vivo, miR-19a-3p agomir stimulated callus transformation and improved the alcohol-impaired fracture healing. Conclusion This study is the first to demonstrate that the miR-19a-3p/FOXF2 axis has a pivotal role in alcohol-impaired fracture healing, and may be a potential therapeutic target. Cite this article: Bone Joint Res 2022;11(6):386–397.

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In utero alcohol exposure exacerbates endothelial protease activity from pial microvessels and impairs GABA interneuron positioning

Cited by 10 publications

References 57 publications

Prenatal alcohol exposure is a leading cause of interneuronopathy in humans

Prenatal alcohol exposure is a leading cause of interneuronopathy in humans

In UteroAlcohol Exposure Impairs Retinal Angiogenesis and the Microvessel-Associated Positioning of Calretinin Interneurons

Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axis

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