Analysis of the Patterning of Cardiac Outflow Tract and Great Arteries with Angiography and Vascular Casting
Department of Medicine, Division of Cardiovascular Medicine, Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. Methods in molecular biology (Clifton, N.J.)
(Impact Factor: 1.29).
01/2012; 843:21-8. DOI: 10.1007/978-1-61779-523-7_3
Formation of the cardiac outflow tract and great arteries involves complex morphogenetic processes, whose abnormities result in several clinically important diseases. Studies of these developmental processes are therefore important for understanding congenital vascular defects. However, the three-dimensional structure of arteries makes it challenging to analyze the pattern of vasculature using conventional histological approaches. Here we describe a vascular casting method to visualize the branching and connections of great arteries in developing embryos as well as in adult mice. This technique can be used to study the development of cardiac outflow tract, semilunar valves, and great arteries as demonstrated previously (Circ Res, 2008; Development 135: 3577-3586, 2008).
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ABSTRACT: Development of the cerebral vessels, pharyngeal arch arteries (PAAs). and cardiac outflow tract (OFT) requires multipotent neural crest cells (NCCs) that migrate from the neural tube to target tissue destinations. Little is known about how mammalian NCC development is orchestrated by gene programming at the chromatin level, however. Here we show that Brahma-related gene 1 (Brg1), an ATPase subunit of the Brg1/Brahma-associated factor (BAF) chromatin-remodeling complex, is required in NCCs to direct cardiovascular development. Mouse embryos lacking Brg1 in NCCs display immature cerebral vessels, aberrant PAA patterning, and shortened OFT. Brg1 suppresses an apoptosis factor, Apoptosis signal-regulating kinase 1 (Ask1), and a cell cycle inhibitor, p21(cip1), to inhibit apoptosis and promote proliferation of NCCs, thereby maintaining a multipotent cell reservoir at the neural crest. Brg1 also supports Myosin heavy chain 11 (Myh11) expression to allow NCCs to develop into mature vascular smooth muscle cells of cerebral vessels. Within NCCs, Brg1 partners with chromatin remodeler Chromodomain-helicase-DNA-binding protein 7 (Chd7) on the PlexinA2 promoter to activate PlexinA2, which encodes a receptor for semaphorin to guide NCCs into the OFT. Our findings reveal an important role for Brg1 and its downstream pathways in the survival, differentiation, and migration of the multipotent NCCs critical for mammalian cardiovascular development.
Available from: Bin Zhou
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ABSTRACT: Congenital coronary artery anomalies produce serious events that include syncope, arrhythmias, myocardial infarction, or sudden death. Studying the mechanism of coronary development will contribute to the understanding of the disease and help design new diagnostic or therapeutic strategies. Here, we characterized a new calcineurin-NFAT signaling which specifically functions in the epicardium to regulate the development of smooth muscle wall of the coronary arteries.Methods and ResultsUsing tissue-specific gene deletion, we found that calcineurin-NFAT signals in the embryonic epicardium to direct coronary smooth muscle cell development. The smooth muscle wall of coronary arteries fails to mature in mice with epicardial deletion of calcineurin B1 (Cnb1), and accordingly these mutant mice develop cardiac dysfunction with reduced exercise capacity. Inhibition of calcineurin at various developmental windows shows that calcineurin-NFAT signals within a narrow time window at embryonic day 12.5-13.5 to regulate coronary smooth muscle cell development. Within the epicardium, NFAT transcriptionally activates the expression of Smad2, whose gene product is critical for transducing transforming growth factor β (TGFβ)-Alk5 signaling to control coronary development.
Our findings demonstrate new spatiotemporal and molecular actions of calcineurin-NFAT that dictate coronary arterial wall development and a new mechanism by which calcineurin-NFAT integrates with TGFβ signaling during embryonic development.
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