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: Conditional inactivation of Hif‐1α, guided by ODD‐Luc as a reflection of PHD activity, was used to test the requirement for HIF‐1α in specific developmental windows. Hif‐1αf/f mice crossed with TM‐inducible β‐actinCre mice resulted in efficient recombination of the Hif‐1α floxed allele in E11.5 and E15.5 heart and liver of TM‐treated mice (Figure 3). Embryos from pregnant mice treated with TM at E10.5 were recovered at normal Mendelian ratios at E15.5 (Table 2). Four of 21 Hif‐1αf/f; β‐actinCre+ (conditional knock‐out (cKO) embryos examined at E15.5 (19%) had malposition of the aorta overriding a ventricular septal defect (VSD; Figure 4, Table 3). Another 3 of the 21 embryos (14%) had isolated VSD. All of the abnormal hearts had thinning of the ventricular myocardium. Twelve of the 21 embryos had open chest walls (thorachoschisis). This was observed in embryos with and without heart defects. The cKO embryos were smaller than their Cre− littermates. Littermates that were Cre− were structurally normal (Figure 4A). Embryos from mice injected with TM at E13.5 and examined at E17.5 did not display cardiac or extra‐cardiac structural defects (Table 3). Thus, abrogation of Hif‐1α after E10.5 causes cardiac outlet defects, while abrogation of HIf‐1α after E13.5 does not, establishing E10.5‐E13.5 as a critical window for HIF‐1α activity.
Affiliation: Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD (D.K., S.A.F.).