Sugrue Kelsey F, Zohn Irene E
Institute for Biomedical Sciences, The George Washington University, Washington, District of Columbia.
Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia.
Genesis. 2019 Jul;57(7-8):e23326. doi: 10.1002/dvg.23326. Epub 2019 Jul 12.
While common in the general population, the developmental origins of "normal" anatomic variants of the aortic arch remain unknown. Aortic arch development begins with the establishment of the second heart field (SHF) that contributes to the pharyngeal arch arteries (PAAs). The PAAs remodel during subsequent development to form the mature aortic arch and arch vessels. Retinoic acid signaling involving the biologically active metabolite of vitamin A, plays a key role in multiple steps of this process. Recent work from our laboratory indicates that the E3 ubiquitin ligase Hectd1 is required for full activation of retinoic acid signaling during cardiac development. Furthermore, our study suggested that mild alterations in retinoic acid signaling combined with reduced gene dosage of Hectd1, results in a benign aortic arch variant where the transverse aortic arch is shortened between the brachiocephalic and left common carotid arteries. These abnormalities are preceded by hypoplasia of the fourth PAA. To further explore this interaction, we investigate whether reduced maternal dietary vitamin A intake can similarly influence aortic arch development. Our findings indicate that the incidence of hypoplastic fourth PAAs, as well as the incidence of shortened transverse arch are increased with reduced maternal vitamin A intake during pregnancy. These studies provide new insights as to the developmental origins of these benign aortic arch variants.
虽然主动脉弓“正常”解剖变异在普通人群中很常见，但其发育起源仍不清楚。主动脉弓发育始于第二心脏场（SHF）的建立，该心脏场对咽弓动脉（PAA）有贡献。PAA在随后的发育过程中进行重塑，以形成成熟的主动脉弓和弓血管。涉及维生素A生物活性代谢物的视黄酸信号在这一过程的多个步骤中起关键作用。我们实验室最近的研究表明，E3泛素连接酶Hectd1是心脏发育过程中视黄酸信号完全激活所必需的。此外，我们的研究表明，视黄酸信号的轻度改变与Hectd1基因剂量的减少相结合，会导致一种良性主动脉弓变异，即头臂干和左颈总动脉之间的横行主动脉弓缩短。这些异常之前是第四PAA发育不全。为了进一步探索这种相互作用，我们研究了母体饮食中维生素A摄入量的减少是否同样会影响主动脉弓的发育。我们的研究结果表明，孕期母体维生素A摄入量减少会增加第四PAA发育不全的发生率以及横行主动脉弓缩短的发生率。这些研究为这些良性主动脉弓变异的发育起源提供了新的见解。
