title: Multimodal imaging reveals a role for Akt1 in fetal cardiac development.
abstract: Even though congenital heart disease is the most prevalent malformation, little is known about how mutations affect cardiovascular function during development. Akt1 is a crucial intracellular signaling molecule, affecting cell survival, proliferation, and metabolism. The aim of this study was to determine the role of Akt1 on prenatal cardiac development. In utero echocardiography was performed in fetal wild-type, heterozygous, and Akt1-deficient mice. The same fetal hearts were imaged using ex vivo micro-computed tomography (μCT) and histology. Neonatal hearts were imaged by in vivo magnetic resonance imaging. Additional ex vivo neonatal hearts were analyzed using histology and real-time PCR of all three groups. In utero echocardiography revealed abnormal blood flow patterns at the mitral valve and reduced contractile function of Akt1 null fetuses, while ex vivo μCT and histology unraveled structural alterations such as dilated cardiomyopathy and ventricular septum defects in these fetuses. Further histological analysis showed reduced myocardial capillaries and coronary vessels in Akt1 null fetuses. At neonatal age, Akt1-deficient mice exhibited reduced survival with reduced endothelial cell density in the myocardium and attenuated cardiac expression of vascular endothelial growth factor A and collagen Iα1. To conclude, this study revealed a central role of Akt1 in fetal cardiac function and myocardial angiogenesis inducing fetal cardiomyopathy and reduced neonatal survival. This study links a specific physiological phenotype with a defined genotype, namely Akt1 deficiency, in an attempt to pinpoint intrinsic causes of fetal cardiomyopathies.
authors.affiliation: Biological Regulation, Weizmann Institute of Science Rehovot, Israel ; Biomedical engineering, Eindhoven University of Technology Eindhoven, The Netherlands.
authors.forename: Katrien
authors.initials: K
authors.lastname: Vandoorne
authors.affiliation: Biological Regulation, Weizmann Institute of Science Rehovot, Israel.
authors.forename: Moriel H
authors.initials: MH
authors.lastname: Vandsburger
authors.affiliation: Biological Regulation, Weizmann Institute of Science Rehovot, Israel.
authors.forename: Karen
authors.initials: K
authors.lastname: Weisinger
authors.affiliation: Chemical Research Support, Weizmann Institute of Science Rehovot, Israel.
authors.forename: Vlad
authors.initials: V
authors.lastname: Brumfeld
authors.affiliation: Friedrich Miescher Institute for Biomedical Research Basel, Switzerland.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hemmings
authors.affiliation: Veterinary Resources, Weizmann Institute of Science Rehovot, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Harmelin
authors.affiliation: Biological Regulation, Weizmann Institute of Science Rehovot, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Neeman
keywords: Akt1; echocardiography; fetus; heart; mice