Coordinated regulation of genes of the nitric oxide and endothelin pathways during the development of pulmonary hypertension in fetal lambs
Coordinated regulation of genes of the nitric oxide and endothelin pathways during the development of pulmonary hypertension in fetal lambs
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DOI：
10.1203/00006450-199812000-00001
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发表时间：
1998-12-01
影响因子：
3.6
通讯作者：
Soifer, SJ
中科院分区：
文献类型：
--
作者：
Black, SM;Johengen, MJ;Soifer, SJ
在子宫内结扎动脉导管会导致胎儿和新生儿的肺动脉高压，并改变胎儿和新生羔羊对一氧化氮和内皮素-1的血流动力学反应。为了确定胎儿肺动脉高压是否改变了一氧化氮和内皮素-1途径的基因表达，对7只妊娠123-126d的胎羊进行了动脉导管结扎。分别从对照和结扎胎羊的近足月(138-139d)取肺总RNA和蛋白质，进行核糖核酸酶保护分析和Western blotting。结扎动脉导管与内皮型一氧化氮合酶、可溶性鸟苷环化酶α(1)和β(1)亚基的表达降低及磷酸二酯酶V的表达增加有关。结扎动脉导管还与前内皮素-1m RNA表达增加和内皮素B受体(ETB)m RNA表达降低有关。这些结果表明，一氧化氮途径的基因存在协同调节，从而降低一氧化氮和cGMP的浓度，从而降低肺血管扩张活性。内皮素-1途径的基因也有协同调节，这将增加内皮素-1的浓度，限制ETB受体的激活，从而增加肺血管收缩活性。这些基因表达的改变会增加胎儿肺血管阻力，导致出生后肺动脉高压的发展。
Ligation of the ductus arteriosus in utero produces fetal and neonatal pulmonary hypertension and alterations in the hemodynamic responses to nitric oxide and endothelin-1 in fetal and newborn lambs. To determine whether fetal pulmonary hypertension alters the expression of the genes of the nitric oxide and endothelin-1 pathways, seven fetal lambs (123-126-d gestation) underwent ligation of the ductus arteriosus. Near-term (138-139-d gestation), total lung RNA, and protein were prepared from control and ductal ligation fetal lambs for RNase protection assays and Western blotting. Ligation of the ductus arteriosus was associated with decreased expression of endothelial nitric oxide synthase mRNA and protein, and the alpha(1) and the beta(1) subunits of soluble guanylate cyclase protein; and with increased expression of phosphodiesterase V mRNA. Ligation of the ductus arteriosus was also associated with increased expression of preproendothelin-1 mRNA and with decreased expression of endothelin B receptor (ETB) mRNA. These results suggest that there is coordinated regulation of genes of the nitric oxide pathway, which would decrease nitric oxide and cGMP concentration, thereby decreasing pulmonary vasodilator activity. There is also coordinated regulation of genes of the endothelin-1 pathway, which would increase endothelin-1 concentration and limit ETB receptor activation, thereby increasing pulmonary vasoconstrictor activity. These alterations in gene expression would increase fetal pulmonary vascular resistance; contributing to the development of pulmonary hypertension after birth.