title: Fetal and neonatal iron deficiency but not copper deficiency increases vascular complexity in the developing rat brain.
abstract: OBJECTIVE
  Anemia caused by nutritional deficiencies, such as iron and copper deficiencies, is a global health problem. Iron and copper deficiencies have their most profound effect on the developing fetus/infant, leading to brain development deficits and poor cognitive outcomes. Tissue iron depletion or chronic anemia can induce cellular hypoxic signaling. In mice, chronic hypoxia induces a compensatory increase in brain blood vessel outgrowth. We hypothesized that developmental anemia, due to iron or copper deficiencies, induces angiogenesis/vasculogenesis in the neonatal brain.
  
  
  METHODS
  To test our hypothesis, three independent experiments were performed where pregnant rats were fed iron- or copper-deficient diets from gestational day 2 through mid-lactation. Effects on the neonatal brain vasculature were determined using quantitative real-time polymerase chain reaction to assess mRNA levels of angiogenesis/vasculogenesis-associated genes and GLUT1 immunohistochemistry to assess brain blood vessel density and complexity.
  
  
  RESULTS
  Iron deficiency, but not copper deficiency, increased mRNA expression of brain endothelial cell- and angiogenesis/vasculogenesis-associated genes (i.e. Glut1, Vwf, Vegfa, Ang2, Cxcl12, and Flk1) in the neonatal brain, suggesting increased cerebrovascular density. Iron deficiency also increased hippocampal and cerebral cortical blood vessel branching by 62 and 78%, respectively.
  
  
  CONCLUSIONS
  This study demonstrates increased blood vessel complexity in the neonatal iron-deficient brain, which is likely due to elevated angiogenic/vasculogenic signaling. At least initially, this is probably an adaptive response to maintain metabolic substrate homeostasis in the developing iron-deficient brain. However, this may also contribute to long-term neurodevelopmental deficits.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Bastian
authors.forename: Stephanie
authors.initials: S
authors.lastname: Santarriaga
authors.forename: Thu An
authors.initials: TA
authors.lastname: Nguyen
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Prohaska
authors.forename: Michael K
authors.initials: MK
authors.lastname: Georgieff
authors.forename: Grant W
authors.initials: GW
authors.lastname: Anderson
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000097:blood* / Q000150:complications; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000098:blood supply* / Q000254:growth & development; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000097:blood* / Q000172:deficiency*; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D006454:Hemoglobins / Q000378:metabolism; D006624:Hippocampus / Q000098:blood supply* / Q000254:growth & development; D008297:Male; D009389:Neovascularization, Pathologic / Q000097:blood* / Q000209:etiology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006454:Hemoglobins; D012333:RNA, Messenger; D003300:Copper; D002570:Ceruloplasmin
keywords: Anemia; Angiogenesis; Blood–brain barrier; Brain; Copper deficiency; Development; Iron deficiency; Neovasculogenesis