Ethanol-Induced Alterations in Placental and Fetal Cerebrocortical Annexin-A4 and Cerebral Cavernous Malformation Protein 3 Are Associated With Reductions in Fetal Cortical VEGF Receptor Binding and Microvascular Density
Jegou et al. (2012) have reported prenatal alcohol exposure (PAE)-induced reductions of angiogenesis-related proteins in mouse placenta. These effects were associated with striking alterations in microvascular development in neonatal cerebral cortex. Here, we employed a rat model of moderate PAE to...
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2020.00519/full |
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| author | Daniel D. Savage Martina J. Rosenberg Laurent Coquet Morgan W. Porch Nyika A. Allen Christian Roux Caroline Aligny Thierry Jouenne Bruno J. Gonzalez |
| author_facet | Daniel D. Savage Martina J. Rosenberg Laurent Coquet Morgan W. Porch Nyika A. Allen Christian Roux Caroline Aligny Thierry Jouenne Bruno J. Gonzalez |
| author_sort | Daniel D. Savage |
| collection | DOAJ |
| description | Jegou et al. (2012) have reported prenatal alcohol exposure (PAE)-induced reductions of angiogenesis-related proteins in mouse placenta. These effects were associated with striking alterations in microvascular development in neonatal cerebral cortex. Here, we employed a rat model of moderate PAE to search for additional proteins whose placental and fetal cortical expression is altered by PAE, along with a subsequent examination of fetal cerebral cortical alterations associated with altered protein expression. Long-Evans rat dams voluntarily consumed either a 0 or 5% ethanol solution 4 h each day throughout gestation. Daily ethanol consumption, which resulted in a mean peak maternal serum ethanol concentration of 60.8 mg/dL, did not affect maternal weight gain, litter size, or placental or fetal body weight. On gestational day 20, rat placental: fetal units were removed by Caesarian section. Placental protein expression, analyzed by 2D-PAGE – tandem mass spectroscopy, identified a total of 1,117 protein spots, 20 of which were significantly altered by PAE. To date, 14 of these PAE-altered proteins have been identified. Western blotting confirmed the alterations of two of these placental proteins, namely, annexin-A4 (ANX-A4) and cerebral cavernous malformation protein 3 (CCM-3). Specifically, PAE elevated ANX-A4 and decreased CCM-3 in placenta. Subsequently, these two proteins were measured in fetal cerebral cortex, along with radiohistochemical studies of VEGF binding and histofluorescence studies of microvascular density in fetal cerebral cortex. PAE elevated ANX-A4 and decreased CCM-3 in fetal cerebral cortex, in a pattern similar to the alterations observed in placenta. Further, both VEGF receptor binding and microvascular density and orientation, measures that are sensitive to reduced CCM-3 expression in developing brain, were significantly reduced in the ventricular zone of fetal cerebral cortex. These results suggest that the expression angiogenesis-related proteins in placenta might serve as a biomarker of ethanol-induced alterations in microvascular development in fetal brain. |
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| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-17T10:48:05Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj.art-4cc7e53640974b63a25104a8cdeecd262022-12-21T21:52:03ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2020-06-011410.3389/fnins.2020.00519517849Ethanol-Induced Alterations in Placental and Fetal Cerebrocortical Annexin-A4 and Cerebral Cavernous Malformation Protein 3 Are Associated With Reductions in Fetal Cortical VEGF Receptor Binding and Microvascular DensityDaniel D. Savage0Martina J. Rosenberg1Laurent Coquet2Morgan W. Porch3Nyika A. Allen4Christian Roux5Caroline Aligny6Thierry Jouenne7Bruno J. Gonzalez8Department of Neurosciences, School of Medicine, University of New Mexico, Albuquerque, NM, United StatesDepartment of Neurosciences, School of Medicine, University of New Mexico, Albuquerque, NM, United StatesUMR 6270, CNRS, Normandie University, UNIROUEN, Proteomic Facility PISSARO, Institute for Research and Innovation in Biomedicine, Rouen, FranceDepartment of Neurosciences, School of Medicine, University of New Mexico, Albuquerque, NM, United StatesDepartment of Neurosciences, School of Medicine, University of New Mexico, Albuquerque, NM, United StatesNormandie University, UNIROUEN, INSERM U1245, Normandy Centre for Genomic and Personalized Medicine, Institute for Research and Innovation in Biomedicine, Rouen, FranceNormandie University, UNIROUEN, INSERM U1245, Normandy Centre for Genomic and Personalized Medicine, Institute for Research and Innovation in Biomedicine, Rouen, FranceUMR 6270, CNRS, Normandie University, UNIROUEN, Proteomic Facility PISSARO, Institute for Research and Innovation in Biomedicine, Rouen, FranceNormandie University, UNIROUEN, INSERM U1245, Normandy Centre for Genomic and Personalized Medicine, Institute for Research and Innovation in Biomedicine, Rouen, FranceJegou et al. (2012) have reported prenatal alcohol exposure (PAE)-induced reductions of angiogenesis-related proteins in mouse placenta. These effects were associated with striking alterations in microvascular development in neonatal cerebral cortex. Here, we employed a rat model of moderate PAE to search for additional proteins whose placental and fetal cortical expression is altered by PAE, along with a subsequent examination of fetal cerebral cortical alterations associated with altered protein expression. Long-Evans rat dams voluntarily consumed either a 0 or 5% ethanol solution 4 h each day throughout gestation. Daily ethanol consumption, which resulted in a mean peak maternal serum ethanol concentration of 60.8 mg/dL, did not affect maternal weight gain, litter size, or placental or fetal body weight. On gestational day 20, rat placental: fetal units were removed by Caesarian section. Placental protein expression, analyzed by 2D-PAGE – tandem mass spectroscopy, identified a total of 1,117 protein spots, 20 of which were significantly altered by PAE. To date, 14 of these PAE-altered proteins have been identified. Western blotting confirmed the alterations of two of these placental proteins, namely, annexin-A4 (ANX-A4) and cerebral cavernous malformation protein 3 (CCM-3). Specifically, PAE elevated ANX-A4 and decreased CCM-3 in placenta. Subsequently, these two proteins were measured in fetal cerebral cortex, along with radiohistochemical studies of VEGF binding and histofluorescence studies of microvascular density in fetal cerebral cortex. PAE elevated ANX-A4 and decreased CCM-3 in fetal cerebral cortex, in a pattern similar to the alterations observed in placenta. Further, both VEGF receptor binding and microvascular density and orientation, measures that are sensitive to reduced CCM-3 expression in developing brain, were significantly reduced in the ventricular zone of fetal cerebral cortex. These results suggest that the expression angiogenesis-related proteins in placenta might serve as a biomarker of ethanol-induced alterations in microvascular development in fetal brain.https://www.frontiersin.org/article/10.3389/fnins.2020.00519/fullethanolplacentacerebral cortexcerebral cavernous malformation protein 3annexin-A4fetal alcohol spectrum disorder |
| spellingShingle | Daniel D. Savage Martina J. Rosenberg Laurent Coquet Morgan W. Porch Nyika A. Allen Christian Roux Caroline Aligny Thierry Jouenne Bruno J. Gonzalez Ethanol-Induced Alterations in Placental and Fetal Cerebrocortical Annexin-A4 and Cerebral Cavernous Malformation Protein 3 Are Associated With Reductions in Fetal Cortical VEGF Receptor Binding and Microvascular Density Frontiers in Neuroscience ethanol placenta cerebral cortex cerebral cavernous malformation protein 3 annexin-A4 fetal alcohol spectrum disorder |
| title | Ethanol-Induced Alterations in Placental and Fetal Cerebrocortical Annexin-A4 and Cerebral Cavernous Malformation Protein 3 Are Associated With Reductions in Fetal Cortical VEGF Receptor Binding and Microvascular Density |
| title_full | Ethanol-Induced Alterations in Placental and Fetal Cerebrocortical Annexin-A4 and Cerebral Cavernous Malformation Protein 3 Are Associated With Reductions in Fetal Cortical VEGF Receptor Binding and Microvascular Density |
| title_fullStr | Ethanol-Induced Alterations in Placental and Fetal Cerebrocortical Annexin-A4 and Cerebral Cavernous Malformation Protein 3 Are Associated With Reductions in Fetal Cortical VEGF Receptor Binding and Microvascular Density |
| title_full_unstemmed | Ethanol-Induced Alterations in Placental and Fetal Cerebrocortical Annexin-A4 and Cerebral Cavernous Malformation Protein 3 Are Associated With Reductions in Fetal Cortical VEGF Receptor Binding and Microvascular Density |
| title_short | Ethanol-Induced Alterations in Placental and Fetal Cerebrocortical Annexin-A4 and Cerebral Cavernous Malformation Protein 3 Are Associated With Reductions in Fetal Cortical VEGF Receptor Binding and Microvascular Density |
| title_sort | ethanol induced alterations in placental and fetal cerebrocortical annexin a4 and cerebral cavernous malformation protein 3 are associated with reductions in fetal cortical vegf receptor binding and microvascular density |
| topic | ethanol placenta cerebral cortex cerebral cavernous malformation protein 3 annexin-A4 fetal alcohol spectrum disorder |
| url | https://www.frontiersin.org/article/10.3389/fnins.2020.00519/full |
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