Research of extracellular matrix in the morphogenesis of tracnsposition of the great arteries

首先，我们分析了小鼠大动脉转位模型的形态发生过程。我们发现一对由细胞外基质组成的圆锥状肿胀在流出间隔形成前发育不全和发育异常，流出肿胀缺乏逆时针旋转，形成直的流出间隔。其次，我们观察了注定发生转位的心脏流出道细胞外基质的定位，发现I型胶原、纤维连接蛋白和透明质酸的分布与对照组不同。然后我们观察了整合素4的免疫组织化学分布它是一种纤维连接蛋白的受体。在妊娠第10-12天的小鼠胚胎中，在心脏流入、流出道、神经嵴源性流出间隔、静脉窦间隔和左居维叶导管的心内膜源性间质中均发现了整合素- 4，与纤维连接蛋白的分布一致，提示整合素- 4在心脏形态发生中发挥了积极的作用。然而，在妊娠第9天，整合素- 4似乎没有参与心脏果冻发育不全的诱导。I型胶原蛋白和/或透明质酸受体可能与这一过程有关，然而，这种可能性目前还在研究中。另一方面，如果提前两天注射维甲酸，则会诱发复杂的心脏缺陷，包括左偏性异常，即脏房异质。心脏缺损中出现大动脉转位。小剂量维甲酸可诱发与大动脉关系正常的圆锥截形异常，形成包括大动脉转位在内的矢状截形异常谱。我们计划在这些扩展的转位模型中研究细胞外基质及其受体及其信号转导通路的异常。

First, we analized the morphogenetic process of the mouse model of transposition of the great arteries. We found that a pair of conus swellings, consisted of extracellular matrix, was hypoplastic and dysplatic before outflfow septum formation and that the outflow swellings lacked counterclockwise rotationand geve rise to straight outflow septum. Second, we looked at the localization of extracellular matrix along cardiac outflow tract destined to develop transposition and found that collagen type I,fibronectin and hyaluronaic acid distributed differently from the control. Then we looked at the immunohistochemical distribution of integrin alpha 4 which is a receptor of fibronectin. In the gestation day 10-12 mouse embryos, integrin alpha 4 was found at the endocardium-derived mesenchymes in the cardiac inflow and outflow tract, neural crest-derived outflow septeum, sinus venosus septum and left Cuvier's duct in accordance with the distribution of fibronectin, suggesting the active role role of integrin alpha 4 in the cardiac morphogenesis. However, integrin alpha 4 did not appear to be involved in the induction of hypoplasia of the cardiac jelly at gestation day 9. Receptors of collagen type I and/or hyaluronic acid might be associated with the process, however, this possibility is currently under investigation. On the other hand, by injecting retinoic acid two days earlier, complex heart defects associated with abnormality of leftright sidedness, i.e., viscero-atrial heteriraxy, are induced. Transposition of the great arteries appears among the heart defects. Less dose of rertinoic acid can induce the conotruncal anomalies with normal relation of the great arteries, which form a spectrum of vonotruncal anomalies includes transposition of great arteries. We plan to investigate the abnormality of ectracellular matrices, their receptors and their signal transduction pathways in those extended model of transposition.