Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
J Clin Invest. 2011 Jan;121(1):422-30. doi: 10.1172/JCI44244. Epub 2010 Dec 13.
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.
先天性主动脉瓣畸形较为常见，并与进行性瓣关闭不全和/或狭窄相关。此外，升主动脉和主动脉弓的动脉瘤、缩窄和夹层通常是相关的病变，使患者的管理复杂化，并增加发病率和死亡率。这些相关的主动脉病变通常归因于通过畸形瓣膜的湍流血流导致血管壁的局灶性缺陷。然而，许多外科和病理学研究已经在受影响的患者的整个主动脉弓中发现了广泛的囊性中膜坏死和平滑肌细胞凋亡。在这里，我们提供了一个替代模型的实验证据来解释主动脉血管和瓣膜疾病的关联。我们使用原发性和继发性心脏神经嵴缺陷的小鼠表明，心脏神经嵴对流出道心内膜垫（半月瓣的前体）的贡献对于妊娠晚期瓣膜重塑、间质细胞凋亡和正常瓣膜结构是必需的。神经嵴也被证明有助于升主动脉和主动脉弓壁的平滑肌层。因此，心脏神经嵴的缺陷可导致功能异常的半月瓣和伴发的主动脉弓动脉异常。
