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，在外流隔形成之前，由细胞外基质组成的一对圆锥膨大是发育不良和发育不良的，而流出的膨大缺乏逆时针旋转，并上升到直的流出隔。其次，我们观察了细胞外基质在发生转位的心脏流出道中的定位，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α4的免疫组织化学分布，它是纤维连接蛋白的一种受体。在孕10~12天的小鼠胚胎中，整合素α4分布于心流入流出道心内膜来源的间质、神经沟来源的流出间隔、静脉窦间隔和左Cuvier管，与纤维连接蛋白的分布相一致，提示整合素α4在心脏形态发生中的积极作用。然而，整合素α4似乎没有参与诱导妊娠第9天心脏凝胶发育不良。I型胶原和/或透明质酸受体可能与这一过程有关，然而，这种可能性目前正在研究中。另一方面，提前两天注射维甲酸，会诱发与左右心异常相关的复杂心脏缺陷，即内脏-心房异位。心脏缺陷中出现大动脉转位。小剂量视黄酸可诱发大动脉关系正常的圆锥干畸形，形成包括大动脉转位在内的一系列血管干畸形。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和信号转导途径的异常。

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.