title: Maternal vitamin A deficiency during pregnancy affects vascularized islet development.
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.
authors: Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan; Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
authors: Chiao-Yun
authors: CY
authors: Chien
authors: Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. Electronic address: benlee@ntu.edu.tw.
authors: Hsuan-Shu
authors: HS
authors: Lee
authors: Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan.
authors: Candy Hsin-Hua
authors: CH
authors: Cho
authors: Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan.
authors: Kuo-I
authors: KI
authors: Lin
authors: Centre for Regenerative Medicine and Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom.
authors: David
authors: D
authors: Tosh
authors: Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan; Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan.
authors: Ruei-Ren
authors: RR
authors: Wu
authors: Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan.
authors: Wan-Yu
authors: WY
authors: Mao
authors: Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan; Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan. Electronic address: cnshen@gate.sinica.edu.tw.
authors: Chia-Ning
authors: CN
authors: Shen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001547:Benzaldehydes / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007515:Islets of Langerhans / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D039382:Maternal Nutritional Physiological Phenomena; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011247:Pregnancy; D011897:Random Allocation; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology; D046509:Tissue Culture Techniques; D014212:Tretinoin / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000378:metabolism / Q000473:pathology*
chemical_list: D001547:Benzaldehydes; D001565:Benzoates; D004791:Enzyme Inhibitors; D018168:Receptors, Retinoic Acid; D012176:Retinoids; C055506:4-(diethylamino)benzaldehyde; D014212:Tretinoin; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; D050697:Retinal Dehydrogenase
keywords: All-trans retinoic acid; Islet vascularization; Laminin; Vascular endothelial growth factor; Vitamin A deficiency