Gene-environment interaction demonstrates the vulnerability of the embryonic heart

Dev Biol. 2014 Jul 1;391(1):99-110. doi: 10.1016/j.ydbio.2014.03.005. Epub 2014 Mar 18.


Mammalian embryos develop in a low oxygen environment. The transcription factor hypoxia inducible factor 1a (HIF1α) is a key element in the cellular response to hypoxia. Complete deletion of Hif1α from the mouse conceptus causes extensive placental, vascular and heart defects, resulting in embryonic lethality. However the precise role of Hif1α in each of these organ systems remains unknown. To further investigate, we conditionally-deleted Hif1α from mesoderm, vasculature and heart individually. Surprisingly, deletion from these tissues did not recapitulate the same severe heart phenotype or embryonic lethality. Placental insufficiency, such as occurs in the complete Hif1α null, results in elevated cellular hypoxia in mouse embryos. We hypothesized that subjecting the Hif1α conditional null embryos to increased hypoxic stress might exacerbate the effects of tissue-specific Hif1α deletion. We tested this hypothesis using a model system mimicking placental insufficiency. We found that the majority of embryos lacking Hif1α in the heart died when exposed to non-physiological hypoxia. This was a heart-specific phenomenon, as HIF1α protein accumulated predominantly in the myocardium of hypoxia-stressed embryos. Our study demonstrates the vulnerability of the heart to lowered oxygen levels, and that under such conditions of non-physiological hypoxia the embryo absolutely requires Hif1α to continue normal development. Importantly, these findings extend our understanding of the roles of Hif1α in cardiovascular development.

Keywords: Gene–environment interaction; HIF1a; Heart development; Hypoxia; Mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Hypoxia
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Endothelial Cells / cytology
  • Female
  • Gene Deletion
  • Gene Expression Regulation, Developmental*
  • Gene-Environment Interaction*
  • Genotype
  • Heart / embryology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitosis
  • Myocardium / metabolism
  • Oxygen / metabolism
  • Phenotype
  • Placenta / metabolism
  • Pregnancy


  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Oxygen