Maternal vitamin A deficiency during pregnancy affects vascularized islet development |
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Affiliation: | 1. Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan;2. Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan;3. Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan;4. Centre for Regenerative Medicine and Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom;5. Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan;1. Department of Medicine, University of Louisville, Louisville, KY, United States;2. Core Proteomics Laboratory, University of Louisville, Louisville, KY, United States;1. The United Graduate School of Agricultural Science, Ehime University, Matsuyama, Ehime 790-8566, Japan;2. Graduate School of Agriculture, Ehime University, Matsuyama, Ehime 790-8566, Japan;3. Food and Health Sciences Research Centre, Ehime University, Matsuyama, Ehime 790-8566, Japan;4. Ikata Service Co., Ltd., Ikata, Ehime 769-0421, Japan;1. Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo, Oviedo, Spain;2. Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain |
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Abstract: | Vitamin A deficiency is known to affect 20 million pregnant women worldwide. However, the prenatal effects of maternal vitamin A deficiency on pancreas development have not been clearly determined. The present study examined how maternal vitamin A deficiency affects fetal islet development. Vitamin A-deficient mice were generated by feeding female mice with a chemically defined diet lacking vitamin A prior to mating as well as during pregnancy. We found that maternal vitamin A deficiency during pregnancy affected fetal pancreas development. Although the exocrine differentiation appeared normal, development of islet tissue was impaired. In the pancreas of neonatal mice, only a few endocrine cell clusters were formed, and these cell clusters lacked capillary endothelial cells. To further determine how vitamin A metabolites, such as retinoic acid, regulate vascularized islet development, ex vivo culture of embryonic pancreas either in the presence of 4-diethylaminobenzaldehyde (DEAB; an inhibitor of retinaldehyde dehydrogenase), all-trans retinoic acid (atRA) or retinoic acid receptor agonist (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl] benzoic acid (TTNPB) was carried out. We found that the addition of DEAB blocked vascularization and suppressed β-cell differentiation. Conversely, atRA or TTNPB promoted β-cell differentiation accompanied by enhanced expression of vascular basement component, laminin. We further demonstrated that atRA regulated vascularization via upregulating vascular endothelial growth factor-A (VEGF-A) secretion in embryonic pancreas and treatment with VEGF-A was able to partially rescue vascularization and β-cell differentiation in DEAB-treated embryonic pancreas cultures. The findings explain why maternal vitamin A deficiency affects fetal islet development and support an essential role of retinoid signaling in regulating vascularized islet development. |
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