Limits...
Vulnerability of the developing heart to oxygen deprivation as a cause of congenital heart defects.

Kenchegowda D, Liu H, Thompson K, Luo L, Martin SS, Fisher SA - J Am Heart Assoc (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD (D.K., S.A.F.).

Show MeSH

Related in: MedlinePlus

Persistent truncus arteriosus (PTA), exencephaly, and cleft face in E15.5 mouse embryo with Hif‐1α inactivation in neural crest cells (NCC). Control (Hif‐1αf/f; Wnt1Cre−) and cKO (Hif‐1αf/f; Wnt1Cre+) littermate embryos are shown in whole mount (A and B) and in sections (C through J) from anterior to posterior with respect to the heart. The cKO embryo (B) is smaller than control (A). The cKO exhibits PTA Type 1, in which the aorta (ao) and pulmonary artery (pa) share a common lumen originating above a single semilunar valve (D and F). H, More posteriorly is persistence of AV cushion mesenchyme with a VSD and (J) a large ASD. The ventricular myocardium is thinned. Scale bars: (A and B) 3000 μm (C through J) 500 μm. ASD indicates atrial septal defect; cKO, conditional knock‐out; Hif, hypoxia‐inducible transcription factor; LV, left ventricle; RV, right ventricle; VSD, ventricular septal defect.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4309110&req=5

fig05: Persistent truncus arteriosus (PTA), exencephaly, and cleft face in E15.5 mouse embryo with Hif‐1α inactivation in neural crest cells (NCC). Control (Hif‐1αf/f; Wnt1Cre−) and cKO (Hif‐1αf/f; Wnt1Cre+) littermate embryos are shown in whole mount (A and B) and in sections (C through J) from anterior to posterior with respect to the heart. The cKO embryo (B) is smaller than control (A). The cKO exhibits PTA Type 1, in which the aorta (ao) and pulmonary artery (pa) share a common lumen originating above a single semilunar valve (D and F). H, More posteriorly is persistence of AV cushion mesenchyme with a VSD and (J) a large ASD. The ventricular myocardium is thinned. Scale bars: (A and B) 3000 μm (C through J) 500 μm. ASD indicates atrial septal defect; cKO, conditional knock‐out; Hif, hypoxia‐inducible transcription factor; LV, left ventricle; RV, right ventricle; VSD, ventricular septal defect.

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.


Vulnerability of the developing heart to oxygen deprivation as a cause of congenital heart defects.

Kenchegowda D, Liu H, Thompson K, Luo L, Martin SS, Fisher SA - J Am Heart Assoc (2014)

Persistent truncus arteriosus (PTA), exencephaly, and cleft face in E15.5 mouse embryo with Hif‐1α inactivation in neural crest cells (NCC). Control (Hif‐1αf/f; Wnt1Cre−) and cKO (Hif‐1αf/f; Wnt1Cre+) littermate embryos are shown in whole mount (A and B) and in sections (C through J) from anterior to posterior with respect to the heart. The cKO embryo (B) is smaller than control (A). The cKO exhibits PTA Type 1, in which the aorta (ao) and pulmonary artery (pa) share a common lumen originating above a single semilunar valve (D and F). H, More posteriorly is persistence of AV cushion mesenchyme with a VSD and (J) a large ASD. The ventricular myocardium is thinned. Scale bars: (A and B) 3000 μm (C through J) 500 μm. ASD indicates atrial septal defect; cKO, conditional knock‐out; Hif, hypoxia‐inducible transcription factor; LV, left ventricle; RV, right ventricle; VSD, ventricular septal defect.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4309110&req=5

fig05: Persistent truncus arteriosus (PTA), exencephaly, and cleft face in E15.5 mouse embryo with Hif‐1α inactivation in neural crest cells (NCC). Control (Hif‐1αf/f; Wnt1Cre−) and cKO (Hif‐1αf/f; Wnt1Cre+) littermate embryos are shown in whole mount (A and B) and in sections (C through J) from anterior to posterior with respect to the heart. The cKO embryo (B) is smaller than control (A). The cKO exhibits PTA Type 1, in which the aorta (ao) and pulmonary artery (pa) share a common lumen originating above a single semilunar valve (D and F). H, More posteriorly is persistence of AV cushion mesenchyme with a VSD and (J) a large ASD. The ventricular myocardium is thinned. Scale bars: (A and B) 3000 μm (C through J) 500 μm. ASD indicates atrial septal defect; cKO, conditional knock‐out; Hif, hypoxia‐inducible transcription factor; LV, left ventricle; RV, right ventricle; VSD, ventricular septal defect.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD (D.K., S.A.F.).

Show MeSH
Related in: MedlinePlus