Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves

• Published in: The Journal of clinical investigation Vol. 121; no. 1; pp. 422 - 430
• Main Authors: Jain, Rajan, Engleka, Kurt A, Rentschler, Stacey L, Manderfield, Lauren J, Li, Li, Yuan, Lijun, Epstein, Jonathan A
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-01-2011
• Subjects: Aneurysms; Animals; Aortic Valve - abnormalities; Aortic Valve - embryology; Aortic Valve - physiopathology; Apoptosis; Biomedical research; Care and treatment; Congenital diseases; Congenital heart disease; Coronary vessels; Endocardial Cushion Defects - embryology; Endocardial Cushion Defects - physiopathology; Extracellular matrix; Female; Heart; Hemodynamics; Humans; Mice; Mice, Mutant Strains; Models, Cardiovascular; Mutation; Neural crest; Neural Crest - abnormalities; Neural Crest - embryology; Neural Crest - physiopathology; Paired Box Transcription Factors - deficiency; Paired Box Transcription Factors - genetics; PAX3 Transcription Factor; Physiological aspects; Pregnancy; Receptors, Notch - genetics; Receptors, Notch - physiology; Signal Transduction; Smooth muscle; Veins & arteries; United States; China
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI44244

Congenital anomalies of the aortic valve are common and are associated with progressive valvular insufficiency and/or stenosis. In addition, aneurysm, coarctation, and dissection of the ascending aorta and aortic arch are often associated conditions that complicate patient management and increase morbidity and mortality. These associated aortopathies are commonly attributed to turbulent hemodynamic flow through the malformed valve leading to focal defects in the vessel wall. However, numerous surgical and pathological studies have identified widespread cystic medial necrosis and smooth muscle apoptosis throughout the aortic arch in affected patients. Here, we provide experimental evidence for an alternative model to explain the association of aortic vessel and valvular disease. Using mice with primary and secondary cardiac neural crest deficiencies, we have shown that neural crest contribution to the outflow endocardial cushions (the precursors of the semilunar valves) is required for late gestation valvular remodeling, mesenchymal apoptosis, and proper valve architecture. Neural crest was also shown to contribute to the smooth muscle layer of the wall of the ascending aorta and aortic arch. Hence, defects of cardiac neural crest can result in functionally abnormal semilunar valves and concomitant aortic arch artery abnormalities.