Hypoxia and fetal heart development

Abstract

Fetal hearts show a remarkable ability to develop under hypoxic conditions. The metabolic flexibility of fetal hearts allows sustained development under low oxygen conditions. In fact, hypoxia is critical for proper myocardial formation. Particularly, hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor play central roles in hypoxia-dependent signaling in fetal heart formation, impacting embryonic outflow track remodeling and coronary vessel growth. Although HIF is not the only gene involved in adaptation to hypoxia, its role places it as a central figure in orchestrating events needed for adaptation to hypoxic stress. Although "normal" hypoxia (lower oxygen tension in the fetus as compared with the adult) is essential in heart formation, further abnormal hypoxia in utero adversely affects cardiogenesis. Prenatal hypoxia alters myocardial structure and causes a decline in cardiac performance. Not only are the effects of hypoxia apparent during the perinatal period, but prolonged hypoxia in utero also causes fetal programming of abnormality in the heart's development. The altered expression pattern of cardioprotective genes such as protein kinase c epsilon, heat shock protein 70, and endothelial nitric oxide synthase, likely predispose the developing heart to increased vulnerability to ischemia and reperfusion injury later in life. The events underlying the long-term changes in gene expression are not clear, but likely involve variation in epigenetic regulation.

Fig. (1). The effect of hypoxia on fetal heart development

1. Insufficient exposure to “normal” hypoxia reduces the expression of key genes (i.e. HIF-α, VEGF) needed for heart and vessels formation. 2. Adequate exposure to “normal” hypoxia ensures expression of hypoxia dependent genes needed for vasculogenesis, angiogenesis and fetal heart remodeling. 3. Chronic exposure to moderate “abnormal” hypoxia can lead to programming of cardioprotective genes, which may decrease the ability of heart to adapt to stresses later in life. 4. Exposure to more severe “abnormal” hypoxia can significantly affect fetal cardiomyocytes development, which can lead to cardiomyopathy.

Fig. (2). Plausible mechanisms for hypoxia-induce down-regulation of cardioprotective genes in hearts

Hypoxia causes the stabilization of HIF-1α and increased ROS production in fetal hearts. These events either act in collusion or independently to cause the recruitment of epigenetic modifiers, i.e. DNA methyltransferase (DNMT) or histone deacetylases (HDAC). These modifiers increase methylation of promoter at transcription factor binding sites and deacetylate histone residues resulting in the decreased transcription of cardioprotective genes (ex. PKCε, HSP70) and decreased cardioprotection in the long-term.