1. Gene–environment interaction demonstrates the vulnerability of the embryonic heart
- Author
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Alexander James, Hongjun Shi, Stuart M. Grieve, Bogdan E. Chapman, Victoria C. O׳Reilly, Richard P. Harvey, Gavin Chapman, Randall S. Johnson, Kylie Lopes Floro, Jost I. Preis, Sally L. Dunwoodie, and Duncan B. Sparrow
- Subjects
Mouse ,Placenta ,Heart development ,Mice ,0302 clinical medicine ,Pregnancy ,Conceptus ,Hypoxia ,Genetics ,0303 health sciences ,Embryonic heart ,Gene Expression Regulation, Developmental ,Heart ,Cell Hypoxia ,Cell biology ,Phenotype ,Hypoxia-inducible factors ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,Genotype ,Mitosis ,Mice, Transgenic ,Placental insufficiency ,Biology ,HIF1a ,Article ,03 medical and health sciences ,medicine ,Animals ,Gene–environment interaction ,Molecular Biology ,Alleles ,Cell Proliferation ,030304 developmental biology ,Cell Nucleus ,Myocardium ,Endothelial Cells ,Cell Biology ,Hypoxia (medical) ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Embryonic stem cell ,Mice, Inbred C57BL ,Oxygen ,HIF1A ,Gene-Environment Interaction ,Gene Deletion ,Developmental Biology - Abstract
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.
- Published
- 2014
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