Ethanol Gestational Exposure Impairs Vascular Development and Endothelial Potential to Control BBB-Associated Astrocyte Function in the Developing Cerebral Cortex.
Ethanol consumption during pregnancy or lactation period can induce permanent damage to the development of the central nervous system (CNS), resulting in fetal alcohol spectrum disorders (FASD). CNS development depends on proper neural cells and blood vessel (BV) development and blood-brain barrier (BBB) establishment; however, little is known about how ethanol affects these events. Here, we investigated the impact of ethanol exposure to endothelial cells (ECs) function and to ECs interaction with astrocytes in the context of BBB establishment. Cerebral cortex of newborn mice exposed in utero to ethanol (FASD model) presented a hypervascularized phenotype, revealed by augmented vessel density, length, and branch points. Further, aberrant distribution of the tight junction ZO-1 protein along BVs and increased rates of perivascular astrocytic endfeet around BVs were observed. In vitro exposure of human brain microcapillary ECs (HBMEC) to ethanol significantly disrupted ZO-1 distribution, decreased Claudin-5 and GLUT-1 expression and impaired glucose uptake, and increased nitric oxide secretion. These events were accompanied by upregulation of angiogenesis-related secreted proteins by ECs in response to ethanol exposure. Treatment of cortical astrocytes with conditioned medium (CM) from ethanol exposed ECs, upregulated astrocyte's expression of GFAP, Cx43, and Lipocalin-2 genes, as well as the pro-inflammatory genes, IL-1beta, IL-6, and TNF-alpha, which was accompanied by NF-kappa B protein nuclear accumulation. Our findings suggest that ethanol triggers a dysfunctional phenotype in brain ECs, leading to impairment of cortical vascular network formation, and promotes ECs-induced astrocyte dysfunction, which could dramatically affect BBB establishment in the developing brain.
['Siqueira|Michele|M|', 'Araujo|Ana Paula Bérgamo|APB|', 'Gomes|Flávia Carvalho Alcantara|FCA|', 'Stipursky|Joice|J|https://orcid.org/0000-0002-7917-6425']
D000818:Animals D000831:Animals, Newborn D001253:Astrocytes D001808:Blood Vessels D001812:Blood-Brain Barrier D002540:Cerebral Cortex D042783:Endothelial Cells D000431:Ethanol D005260:Female D063647:Fetal Alcohol Spectrum Disorders D020869:Gene Expression Profiling D005786:Gene Expression Regulation D006801:Humans D051379:Mice D018919:Neovascularization, Physiologic D010641:Phenotype D011247:Pregnancy D011297:Prenatal Exposure Delayed Effects
Ethanol Astrocytes Blood-brain barrier Angiogenesis Cerebral cortex development