Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Congenital heart disease (CHD) is an enigma. It is the most common human birth defect and yet, even with the application of modern genetic and genomic technologies, only a minority of cases can be explained genetically. This is because environmental stressors also cause CHD. Here we propose a plausible non-genetic mechanism for induction of CHD by environmental stressors. We show that exposure of mouse embryos to short-term gestational hypoxia induces the most common types of heart defect. This is mediated by the rapid induction of the unfolded protein response (UPR), which profoundly reduces FGF signaling in cardiac progenitor cells of the second heart field. Thus, UPR activation during human pregnancy might be a common cause of CHD. Our findings have far-reaching consequences because the UPR is activated by a myriad of environmental or pathophysiological conditions. Ultimately, our discovery could lead to preventative strategies to reduce the incidence of human CHD.

Original publication




Journal article



Publication Date





2561 - 2572


FGF signaling, Heart development, Hypoxia, Unfolded protein response, Animals, Apoptosis, Cell Differentiation, Cell Hypoxia, Cell Proliferation, Embryo, Mammalian, Female, Fibroblast Growth Factors, Heart Defects, Congenital, Mice, Inbred C57BL, Oxygen, Phenotype, Pregnancy, Protein Biosynthesis, Receptor, Fibroblast Growth Factor, Type 1, Signal Transduction, Stress, Physiological, Unfolded Protein Response