Stenmark K R, Durmowicz A G, Roby J D, Mecham R P, Parks W C
University of Colorado Health Sciences Center, Denver 80262.
J Clin Invest. 1994 Mar;93(3):1234-42. doi: 10.1172/JCI117077.
Neonatal hypoxic pulmonary hypertension causes increases and spatial changes in tropoelastin expression in pulmonary arteries. However, it is not clear if this is due to recruitment of quiescent smooth muscle cells (SMC) into an elastin-producing phenotype or persistence of the fetal pattern of tropoelastin gene expression. We evaluated the distribution and relative concentration of tropoelastin mRNA in intralobar pulmonary arteries from late gestation fetuses and in animals exposed to hypobaric hypoxia (430 mmHg) from birth for 1, 3, 7, or 14 d, as well as in age-matched and adult room air-breathing controls. In situ hybridization demonstrated that tropoelastin mRNA was distributed throughout the entire radius of the pulmonary vessel wall in the fetus and newborn calf. By 15 d of age, only cells in the inner third of the media expressed tropoelastin mRNA, and by adulthood no tropoelastin mRNA was detected in the vessel wall. These findings demonstrated that tropoelastin expression shuts off in a spatially specific pattern, moving from the abluminal to the luminal side of the medial in the neonatal pulmonary artery when pressures and resistance are falling. In the aorta of 15-d-old calves, tropoelastin mRNA expression was seen equally throughout the media, indicating tissue-specific regulation of elastin in the neonatal period. In contrast, intralobar pulmonary arteries from calves exposed to hypoxia, which prevented the normal postnatal decline in pulmonary artery pressure, maintained the fetal pattern and levels of tropoelastin mRNA expression at all time points. Thus, rather than causing a recruitment of SMC into an elastin-producing phenotype, neonatal pulmonary hypertension caused a persistence of the fetal pattern of tropoelastin expression in medial SMC. Cell-free translation showed that the same tropoelastin isoforms were made by mRNA from control and hypertensive calves and, unlike the ligamentum nuchae, did not change during the transition from fetal to neonatal life. We conclude that pulmonary hypertension in the neonate perturbs the normal postpartum repression of tropoelastin expression resulting in a persistence of the fetal spacial and isoform patterns of tropoelastin gene expression.
新生儿缺氧性肺动脉高压会导致肺动脉中原弹性蛋白表达增加及空间变化。然而，尚不清楚这是由于静止的平滑肌细胞（SMC）转变为产生弹性蛋白的表型，还是由于原弹性蛋白基因表达的胎儿模式持续存在。我们评估了妊娠晚期胎儿叶内肺动脉以及出生后暴露于低压缺氧环境（430 mmHg）1、3、7或14天的动物的叶内肺动脉中原弹性蛋白mRNA的分布和相对浓度，同时也评估了年龄匹配的和成年呼吸空气的对照组。原位杂交显示，原弹性蛋白mRNA在胎儿和新生小牛的肺血管壁整个半径范围内均有分布。到15日龄时，仅中膜内侧三分之一的细胞表达原弹性蛋白mRNA，到成年时，血管壁中未检测到原弹性蛋白mRNA。这些发现表明，当压力和阻力下降时，原弹性蛋白表达以空间特异性模式关闭，在新生儿肺动脉中从中膜的腔外侧向腔内移动。在15日龄小牛的主动脉中，整个中膜均可见原弹性蛋白mRNA表达，表明新生儿期弹性蛋白存在组织特异性调节。相比之下，暴露于缺氧环境的小牛的叶内肺动脉，由于阻止了出生后肺动脉压力的正常下降，在所有时间点均维持了原弹性蛋白mRNA表达的胎儿模式和水平。因此，新生儿肺动脉高压并非导致SMC转变为产生弹性蛋白的表型，而是导致中膜SMC中原弹性蛋白表达的胎儿模式持续存在。无细胞翻译显示，来自对照小牛和高血压小牛的mRNA产生相同的原弹性蛋白异构体，并且与项韧带不同，在从胎儿到新生儿期的转变过程中没有变化。我们得出结论，新生儿肺动脉高压扰乱了产后原弹性蛋白表达的正常抑制，导致原弹性蛋白基因表达的胎儿空间和异构体模式持续存在。
