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

Abstract

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.

Hypoxia as a Driving Force of Pluripotent Stem Cell Reprogramming and Differentiation to Endothelial Cells

“…Over the time of 8 weeks (duration of the embryogenesis in humans) a complex, however, not fully functioning organism grows out of a single-celled zygote [10]. Embryogenesis occurs in relatively hypoxic conditions due to the rapid cell proliferation as well as increased oxygen demand and consumption, which is not yet supported by the maternal circulation [11][12][13] (Figure 2). The biology of the HIF-3 factor is still not fully discovered as its multiple variants being the result of the utilization of various promoters, different transcription initiation sites, and alternative splicing exist [7].…”

“…Over the time of 8 weeks (duration of the embryogenesis in humans) a complex, however, not fully functioning organism grows out of a single-celled zygote [10]. Embryogenesis occurs in relatively hypoxic conditions due to the rapid cell proliferation as well as increased oxygen demand and consumption, which is not yet supported by the maternal circulation [11][12][13] (Figure 2).…”

Generation of a hypoxia‐sensing mouse model

“…Hypoxia occurs during embryonic development (Dunwoodie, ; Llurba Olive, Xiao, Natale, & Fisher, ; Mitchell & Yochim, ; Rodesch, Simon, Donner, & Jauniaux, ). Genetic deletion of either Hif1a or Hif1b in mouse models leads to embryonal lethality around E10.5 (Iyer et al, ; Kozak, Abbott, & Hankinson, ; Maltepe, Schmidt, Baunoch, Bradfield, & Simon, ; Ryan et al, ).…”

Can Erythropoietin Reduce Hypoxemic Neurological Damages in Neonates With Congenital Heart Defects?

“…The activation of HIF has been suggested to play a role in fetal development, and if timed with maternal hypoxia or placental insufficiency, may contribute to CHD morphology ( Bishop and Ratcliffe, 2015 ; Llurba Olive et al, 2018 ). Additionally, HIF-1α promotes the expression of various genes to assist cells in hypoxic and ischemic conditions including vascular endothelial growth factor ( VEGF ) and EPO , and may directly protect neurons ( Zhang et al, 2004 ).…”