Oxygen and lack of oxygen in fetal and placental development, feto–placental coupling, and congenital heart defects

Elisa Llurba Olive, Emily Xiao, David R. Natale, Steven A. Fisher

Research output: Contribution to journalReview articleResearchpeer-review

17 Citations (Scopus)


© 2018 Wiley Periodicals, Inc. Low oxygen concentration (hypoxia) is part of normal embryonic development, yet the situation is complex. Oxygen (O2) is a janus gas with low levels signaling through hypoxia-inducible transcription factor (HIF) that are required for development of fetal and placental vasculature and fetal red blood cells. This results in coupling of fetus and mother around midgestation as a functional feto-placental unit (FPU) for O2 transport, which is required for continued growth and development of the fetus. Defects in these processes may leave the developing fetus vulnerable to O2 deprivation or other stressors during this critical midgestational transition when common septal and conotruncal heart defects (CHDs) are likely to arise. Recent human epidemiological and case–control studies support an association between placental dysfunction, manifest as early onset pre-eclampsia (PE) and increased serum bio-markers, and CHD. Animal studies support this association, in particular those using gene inactivation in the mouse. Sophisticated methods for gene inactivation, cell fate mapping, and a quantitative bio-reporter of O2 concentration support the premise that hypoxic stress at critical stages of development leads to CHD. The secondary heart field contributing to the cardiac outlet is a key target, with activation of the un-folded protein response and abrogation of FGF signaling or precocious activation of a cardiomyocyte transcriptional program for differentiation, suggested as mechanisms. These studies provide a strong foundation for further study of feto–placental coupling and hypoxic stress in the genesis of human CHD.
Original languageEnglish
Pages (from-to)1517-1530
JournalBirth Defects Research
Issue number20
Publication statusPublished - 1 Dec 2018


  • ganogenesis
  • HIF
  • hypoxia
  • outflow tractor
  • pre-eclampsia
  • septum
  • spiral arteries
  • VEGF


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