Coordinated regulation of genes of the nitric oxide and endothelin pathways during the development of pulmonary hypertension in fetal lambs

Stephen M. Black, Michael J. Johengen, Scott J. Soifer

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

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 α1 and the β1 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 (ET(B)) 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 ET(B) 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.

Original languageEnglish (US)
Pages (from-to)821-830
Number of pages10
JournalPediatric Research
Volume44
Issue number6
DOIs
StatePublished - Jan 1 1998

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Endothelins
Endothelin-1
Ductus Arteriosus
Pulmonary Hypertension
Ligation
Nitric Oxide
Endothelin B Receptors
Messenger RNA
Genes
Lung
Type 5 Cyclic Nucleotide Phosphodiesterases
Gene Expression
Pregnancy
Proteins
Nitric Oxide Synthase Type III
Vasoconstrictor Agents
Ribonucleases
Vasodilator Agents
Vascular Resistance
Hemodynamics

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Coordinated regulation of genes of the nitric oxide and endothelin pathways during the development of pulmonary hypertension in fetal lambs. / Black, Stephen M.; Johengen, Michael J.; Soifer, Scott J.

In: Pediatric Research, Vol. 44, No. 6, 01.01.1998, p. 821-830.

Research output: Contribution to journalArticle

Black, Stephen M. ; Johengen, Michael J. ; Soifer, Scott J. / Coordinated regulation of genes of the nitric oxide and endothelin pathways during the development of pulmonary hypertension in fetal lambs. In: Pediatric Research. 1998 ; Vol. 44, No. 6. pp. 821-830.
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