Hyperplastic conotruncal endocardial cushions and transposition of great arteries in perlecan-null mice
Hyperplastic conotruncal endocardial cushions and transposition of great arteries in perlecan-null mice
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DOI：
10.1161/01.res.0000026056.81424.da
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发表时间：
2002-07-26
影响因子：
20.1
通讯作者：
Muñoz-Chápuli, R
中科院分区：
文献类型：
--
作者：
Costell, M;Carmona, R;Muñoz-Chápuli, R
Perlecan是一种硫酸肝素蛋白多糖，在发育过程中在细胞周围基质和基底膜中大量表达。小鼠的perlecan基因失活在两个发育阶段是致命的：大约在10岁左右和出生前后。我们报告了高发生率的畸形心脏流出道在perlecan缺陷胚胎。15个晚期胚胎中有11个（73%）被诊断为完全性大动脉转位。这11个胚胎中有3个也出现了。半月瓣畸形。当野生型胚胎开始心内膜-间充质转化时，在E9.5突变胚胎中流出道的间充质细胞异常丰富。在E10.5时，突变胚胎缺乏明确的螺旋心内膜脊，过多的间充质细胞有时阻塞流出道管腔。这种异常间质大多表达平滑肌细胞特异性a-肌动蛋白异构体，这是小鼠流出道神经嵴的标志。在野生型胚胎中，perlecan存在于心肌和心内膜的基底表面，以及周围假定的神经嵴细胞。我们认为，在圆锥锥体发育的早期阶段，间质的过剩阻止了螺旋脊的形成和分隔复合体的旋转，以实现协调的脑室-动脉连接。观察到的间充质细胞数量过多可能是由于神经嵴细胞不受控制的迁移，这些细胞会过早到达心脏。因此，perlecan参与了流出道间充质细胞群大小的控制，强调了细胞外基质在心脏形态发生中的重要性。
Perlecan is a heparan-sulfate proteoglycan abundantly expressed in pericellular matrices and basement membranes during development. Inactivation of the perlecan gene in mice is lethal at two developmental stages: around E10 and around birth. We report a high incidence of malformations of the cardiac outflow tract in perlecan-deficient embryos. Complete transposition of great arteries was diagnosed in 11 out of 15 late embryos studied (73%). Three of these 11 embryos also showed. malformations of semilunar valves. Mesenchymal cells in the outflow tract were abnormally abundant in mutant embryos by E9.5, when the endocardial-mesenchymal transformation starts in wild-type embryos. At E10.5, mutant embryos lacked well-defined spiral endocardial ridges, and the excess of mesenchymal cells obstructed sometimes the outflow tract lumen. Most of this anomalous mesenchyme expressed the smooth muscle cell-specific a-actin isoform, a marker of the neural crest in the outflow tract of the mouse. In wild-type embryos, perlecan is present in the basal surface of myocardium and endocardium, as well as surrounding presumptive neural crest cells. We suggest that the excess of mesenchyme at the earlier stages of conotruncal development precludes the formation of the spiral ridges and the rotation of the septation complex in order to achieve a concordant ventriculoarterial connection. The observed mesenchymal overpopulation might be due to an uncontrolled migration of neural crest cells, which would arrive prematurely to the heart. Thus, perlecan is involved in the control of the outflow tract mesenchymal population size, underscoring the importance of the extracellular matrix in cardiac morphogenesis.