Yang J, Zeini M, Lin CY, Lin CJ, Xiong Y, Shang C, Han P, Li W, Quertermous T, Zhou B, Chang CP
Epicardial Calcineurin-NFAT Signals Through Smad2 to Direct Coronary Smooth Muscle Cell and Arterial Wall Development.
Cardiovascular Research. 2013 Aug 14;
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.