RRC ID 47688
Author Girault V, Gilard V, Marguet F, Lesueur C, Hauchecorne M, Ramdani Y, Laquerrière A, Marret S, Jégou S, Gonzalez BJ, Brasse-Lagnel C, Bekri S.
Title Prenatal alcohol exposure impairs autophagy in neonatal brain cortical microvessels.
Journal Cell Death Dis
Abstract Brain developmental lesions are a devastating consequence of prenatal alcohol exposure (PAE). We recently showed that PAE affects cortical vascular development with major effects on angiogenesis and endothelial cell survival. The underlying molecular mechanisms of these effects remain poorly understood. This study aimed at characterizing the ethanol exposure impact on the autophagic process in brain microvessels in human fetuses with fetal alcohol syndrome (FAS) and in a PAE mouse model. Our results indicate that PAE induces an increase of autophagic vacuole number in human fetal and neonatal mouse brain cortical microvessels. Subsequently, ex vivo studies using green fluorescent protein (GFP)-LC3 mouse microvessel preparations revealed that ethanol treatment alters autophagy in endothelial cells. Primary cultures of mouse brain microvascular endothelial cells were used to characterize the underlying molecular mechanisms. LC3 and p62 protein levels were significantly increased in endothelial cells treated with 50 mM ethanol. The increase of autophagic vacuole number may be due to excessive autophagosome formation associated with the partial inhibition of the mammalian target of rapamycin pathway upon ethanol exposure. In addition, the progression from autophagosomes to autolysosomes, which was monitored using autophagic flux inhibitors and mRFP-EGFP vector, showed a decrease in the autolysosome number. Besides, a decrease in the Rab7 protein level was observed that may underlie the impairment of autophagosome-lysosome fusion. In addition, our results showed that ethanol-induced cell death is likely to be mediated by decreased mitochondrial integrity and release of apoptosis-inducing factor. Interestingly, incubation of cultured cells with rapamycin prevented ethanol effects on autophagic flux, ethanol-induced cell death and vascular plasticity. Taken together, these results are consistent with autophagy dysregulation in cortical microvessels upon ethanol exposure, which could contribute to the defects in angiogenesis observed in patients with FAS. Moreover, our results suggest that rapamycin represents a potential therapeutic strategy to reduce PAE-related brain developmental disorders.
Volume 8(2)
Pages e2610
Published 2017-2-9
DOI 10.1038/cddis.2017.29
PII cddis201729
PMID 28182007
PMC PMC5386476
MeSH Animals Autophagosomes / drug effects Autophagosomes / metabolism Autophagy / drug effects* Brain / drug effects* Brain / metabolism Brain / pathology Endothelial Cells / drug effects Endothelial Cells / metabolism Endothelial Cells / pathology Ethanol / adverse effects* Female Fetal Alcohol Spectrum Disorders / metabolism Fetal Alcohol Spectrum Disorders / pathology Humans Lysosomes / drug effects Lysosomes / metabolism Mice Mice, Inbred C57BL Mice, Transgenic Microtubule-Associated Proteins / metabolism Microvessels / drug effects* Microvessels / metabolism Microvessels / pathology Mitochondria / drug effects Mitochondria / metabolism Mitochondria / pathology Models, Animal Pregnancy Prenatal Exposure Delayed Effects / chemically induced* Prenatal Exposure Delayed Effects / metabolism Prenatal Exposure Delayed Effects / pathology* RNA-Binding Proteins / metabolism Sirolimus / pharmacology
IF 6.304
Times Cited 11
Mice RBRC00806