Fetal and neonatal iron deficiency but not copper deficiency increases vascular complexity in the developing rat brain

Thomas W Bastian, Stephanie Santarriaga, Thu An Nguyen, Joseph R. Prohaska, Michael K Georgieff, Grant W Anderson

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Objectives: 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 a so increased hippocampal and cerebral cortical blood vessel branching by 62 and 78%, respectively. Discussion: 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.

Original languageEnglish (US)
Pages (from-to)365-375
Number of pages11
JournalNutritional Neuroscience
Issue number8
StatePublished - Nov 2015

Bibliographical note

Publisher Copyright:
© W. S. Maney & Son Ltd 2015.


  • Anemia
  • Angiogenesis
  • Blood–brain barrier
  • Brain
  • Copper deficiency
  • Development
  • Iron deficiency
  • Neovasculogenesis


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