Bökenkamp Regina, van Brempt Ronald, van Munsteren Jacoba Cornelia, van den Wijngaert Ilse, de Hoogt Ronald, Finos Livio, Goeman Jelle, Groot Adriana Cornelia Gittenberger-de, Poelmann Robert Eugen, Blom Nicolaas Andreas, DeRuiter Marcus Cornelis
Department of Pediatric Cardiology, Leiden University Medical Center, Leiden, The Netherlands ; Department of Intensive Care, Leiden University Medical Center, Leiden, The Netherlands.
Department of Intensive Care, Leiden University Medical Center, Leiden, The Netherlands ; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium.
PLoS One. 2014 Jan 28;9(1):e86892. doi: 10.1371/journal.pone.0086892. eCollection 2014.
Closure of the ductus arteriosus (DA) is a crucial step in the transition from fetal to postnatal life. Patent DA is one of the most common cardiovascular anomalies in children with significant clinical consequences especially in premature infants. We aimed to identify genes that specify the DA in the fetus and differentiate it from the aorta. Comparative microarray analysis of laser-captured microdissected endothelial (ECs) and vascular smooth muscle cells (SMCs) from the DA and aorta of fetal rats (embryonic day 18 and 21) identified vessel-specific transcriptional profiles. We found a strong age-dependency of gene expression. Among the genes that were upregulated in the DA the regulator of the G-protein coupled receptor 5 (Rgs5) and the transcription factor distal-less homeobox 1 (Dlx1) exhibited the highest and most significant level of differential expression. The aorta showed a significant preferential expression of the Purkinje cell protein 4 (Pcp4) gene. The results of the microarray analysis were validated by real-time quantitative PCR and immunohistochemistry. Our study confirms vessel-specific transcriptional profiles in ECs and SMCs of rat DA and aorta. Rgs5 and Dlx1 represent novel molecular targets for the regulation of DA maturation and closure.
动脉导管（DA）的闭合是从胎儿期到出生后生活转变的关键步骤。动脉导管未闭是儿童中最常见的心血管异常之一，具有显著的临床后果，尤其是在早产儿中。我们旨在鉴定在胎儿期指定动脉导管并将其与主动脉区分开的基因。对来自胎鼠（胚胎第18天和21天）的动脉导管和主动脉的激光捕获显微切割的内皮细胞（ECs）和血管平滑肌细胞（SMCs）进行比较微阵列分析，确定了血管特异性转录谱。我们发现基因表达具有强烈的年龄依赖性。在动脉导管中上调的基因中，G蛋白偶联受体5调节剂（Rgs5）和转录因子远端缺失同源盒1（Dlx1）表现出最高且最显著的差异表达水平。主动脉显示出浦肯野细胞蛋白4（Pcp4）基因的显著优先表达。微阵列分析结果通过实时定量PCR和免疫组织化学得到验证。我们的研究证实了大鼠动脉导管和主动脉的内皮细胞和平滑肌细胞中的血管特异性转录谱。Rgs5和Dlx1代表了调节动脉导管成熟和闭合的新分子靶点。
