O'Reilly, Victoria C and Lopes Floro, Kylie and Shi, Hongjun and Chapman, Bogdan E and Preis, Jost I and James, Alexander C and Chapman, Gavin and Harvey, Richard P and Johnson, Randall S and Grieve, Stuart M and Sparrow, Duncan B and Dunwoodie, Sally L (2014) Gene-environment interaction demonstrates the vulnerability of the embryonic heart. Developmental Biology, 391 (1). pp.99-110. ISSN 1095-564X (OA)
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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.
(NHMRC Grants 303705, 404805, 1019776, a514900 and 1042002).
| Item Type: | Article |
|---|---|
| Additional Information: | COPYRIGHT: Elsevier user licence: article cannot be distributed. |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 21 Jan 2016 23:54 |
| Last Modified: | 29 Jun 2016 23:56 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/219 |
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