Maternal vitamin A deficiency during pregnancy affects vascularized islet development

• Published in: The Journal of nutritional biochemistry 2016-10, Vol.36, p.51-59
• Main Authors: Chien, Chiao-Yun, Lee, Hsuan-Shu, Cho, Candy Hsin-Hua, Lin, Kuo-I, Tosh, David, Wu, Ruei-Ren, Mao, Wan-Yu, Shen, Chia-Ning
• Format: Article
• Language: English
• Subjects: All-trans retinoic acid; Animals; Animals, Newborn; Benzaldehydes - pharmacology; Benzoates - pharmacology; Cell Differentiation - drug effects; Embryo, Mammalian - cytology; Embryo, Mammalian - pathology; Enzyme Inhibitors - pharmacology; Female; Fetal Development - drug effects; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Islet vascularization; Islets of Langerhans - blood supply; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Laminin; Maternal Nutritional Physiological Phenomena; Mice, Inbred C57BL; Mice, Transgenic; Neovascularization, Physiologic - drug effects; Pregnancy; Random Allocation; Receptors, Retinoic Acid - agonists; Receptors, Retinoic Acid - antagonists & inhibitors; Receptors, Retinoic Acid - metabolism; Retinal Dehydrogenase - antagonists & inhibitors; Retinal Dehydrogenase - metabolism; Retinoids - pharmacology; Tissue Culture Techniques; Tretinoin - metabolism; Vascular endothelial growth factor; Vitamin A deficiency; Vitamin A Deficiency - metabolism; Vitamin A Deficiency - pathology
• ISSN: 0955-2863; 1873-4847
• DOI: 10.1016/j.jnutbio.2016.07.010

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.