Morphogenesis of outflow tract rotation during cardiac development: The pulmonary push concept

Abstract

Background: Understanding of cardiac outflow tract (OFT) remodeling is essential to explain repositioning of the aorta and pulmonary orifice. In wild type embryos (E9.5-14.5), second heart field contribution (SHF) to the OFT was studied using expression patterns of Islet 1, Nkx2.5, MLC-2a, WT-1, and 3D-reconstructions. Abnormal remodeling was studied in VEGF120/120 embryos. Results: In wild type, Islet 1 and Nkx2.5 positive myocardial precursors formed an asymmetric elongated column almost exclusively at the pulmonary side of the OFT up to the pulmonary orifice. In VEGF120/120 embryos, the Nkx2.5-positive mesenchymal population was disorganized with a short extension along the pulmonary OFT. Conclusions: We postulate that normally the pulmonary trunk and orifice are pushed in a higher and more frontal position relative to the aortic orifice by asymmetric addition of SHF-myocardium. Deficient or disorganized right ventricular OFT expansion might explain cardiac malformations with abnormal position of the great arteries, such as double outlet right ventricle. Developmental Dynamics 241:1413-1422, 2012. V C 2012 Wiley Periodicals, Inc.Key words: cardiac development; outflow tract; gene expression Key findings:The addition of Nkx2.5-positive myocardial precursors from the anterior heart field occurs during normal development in an asymmetrical fashion, predominantly below the left branch of the 6th pharyngeal arch artery. The continued addition of right-sided myocardium during normal development results in movement without spiralization of the OFT in which the pulmonary trunk orifice is pushed in a rightward and anterior direction, a mechanism referred to as ''pulmonary push.'' Deficient or disorganized positioning of the Nkx2.5-positive precursors, as was observed in VEGF120/120 mutants might explain cardiac malformations with side-by-side position of the great arteries, such as double outlet right ventricle.

Bicuspid Aortic Valve Morphology and Associated Cardiovascular Abnormalities in Fetal Turner Syndrome: A Pathomorphological Study

“…Fernandez et al [23] suggested that particularly type 1 BAV results from abnormal neural crest cell behavior. Our data may indicate that also the sidedness of neural crest contributions may be of relevance, as was shown previously for second heart field contributions to the outflow tract [34]. Further study in larger, unselected (non-TS) cohorts is required to support this hypothesis.…”

Capturing structure and function in an embryonic heart with biophotonic tools

“…Because it is much easier to identify and illustrate cardiac defects in 3-D, images of histological sections are often segmented and cardiac structures reconstructed in silico (e.g., Newbern et al, 2008; Scherptong et al, 2012; Briggs et al, 2013) (example in movie Figure 1S in Supplementary Material). The challenge of 3-D reconstruction is that sections are likely to be at slightly different angles and rotations or deformed during the collection of sections on slides so that adjustments of the images must be made by eye or by using computer programs to semi-automatically register the images.…”

AcvR1-mediated BMP signaling in second heart field is required for arterial pole development: Implications for myocardial differentiation and regional identity

“…This could be because specific SHF populations failed to make their normal contribution to the OFT. RV/OFT walls are formed from cells originating in different areas of SHF(Bertrand et al, 2011; Dominguez et al, 2012; Takahashi et al, 2012) and their regional contribution to the tube may act to displace others in relation to the axes of the rest of the heart, i.e., relative ‘rotation’(Bajolle et al, 2006; Scherptong et al, 2012), including forming the distinctive subpulmonary myocardial population essential for normal truncal origin position and proximal trunk wall cells. We observed consistent regions of abnormally thin and thick OFT walls, areas of thickened trunk wall, and an insufficiency of sub-pulmonary myocardium suggesting AcvR1 and BmpR1a-mediated BMP signaling is required for normal formation, location and differentiation of specific SHF cell populations.…”