Vulnerability of the developing heart to oxygen deprivation as a cause of congenital heart defects.
Bottom Line: The heart develops under reduced and varying oxygen concentrations, yet there is little understanding of oxygen metabolism in the normal and mal-development of the heart.ODD-Luc activity decreased in 2 stages, the first corresponding with the formation of a functional cardiovascular system for oxygen delivery at E15.5, and the second after birth consistent with complete oxygenation of the blood and tissues.Low oxygen concentrations and lack of oxygen reserve during a critical phase of heart organogenesis may provide a basis for vulnerability to the development of common septation and conotruncal heart defects.
Affiliation: Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD (D.K., S.A.F.).Show MeSH
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Mentions: The previous experiments defined the role of Hif‐1α in a critical developmental window, but because the β‐actinCre is ubiquitously active, did not define its role in specific cell types that are required for development of the cardiac outlet. To address this, Wnt1Cre was used to inactivate Hif‐1α in NCCs that migrate into the cardiac outlet and are required for the formation of the aortico‐pulmonic septum,7 a region that this and a prior study10 suggested is particularly hypoxic. Embryos were examined at E15.5 to 16.5 after NCCs have migrated into the heart and septation of the heart and OFT are complete. Embryos were recovered at normal Mendelian ratios at E15.5 to 16.5 (Table 2). Six of 26 (23%) E15.5 to 16.5 Hif‐1αf/f; Wnt1Cre+ embryos had defects typical of NCC deficiency (Figure 5, Table 3), including exencephaly and cleft face (Figure 5B). Four of the embryos had persistent truncus arteriosus (PTA Type 1) reflecting failure of septation of a portion of the OFT (Figure 5D) and a single semi‐lunar valve separating the common arterial trunk from the ventricle (Figure 5F). More posteriorly abnormal persistence of the AV cushion mesenchyme is associated with ventricular and atrial septal defects, and ventricular myocardial thinning is also evident (Figures 5H and 5J). Two of the embryos had OFT defects classified as double outlet right ventricle (DORV), in which both aorta and pulmonary artery arise from the right ventricle. All of the abnormal cKO embryos and their hearts were smaller than their littermate controls.
Affiliation: Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD (D.K., S.A.F.).