COORDINATED REGULATION OF GENES OF THE NITRIC-OXIDE AND ENDOTHELIN PATHWAYS DURING THE DEVELOPMENT OF PULMONARY-HYPERTENSION IN FETAL LAMBS

Ligation of the ductus arteriosus in utero produces fetal and neonatal pulmonary hypertension and alterations in the hemodynamic responses t o nitric oxide and endothelin-1 in fetal and newborn lambs. To determi ne whether fetal pulmonary hypertension alters the expression of the g enes of the nitric oxide and endothelin-1 pathways, seven fetal lambs (123-126-d gestation) underwent ligation of the ductus arteriosus. Nea r-term (138-139-d gestation), total lung RNA, and protein were prepare d from control and ductal ligation fetal lambs for RNase protection as says and Western blotting. Ligation of the ductus arteriosus was assoc iated with decreased expression of endothelial nitric oxide synthase m RNA and protein, and the alpha(1) and the beta(1) subunits of soluble guanylate cyclase protein; and with increased expression of phosphodie sterase V mRNA. Ligation of the ductus arteriosus was also associated with increased expression of preproendothelin-1 mRNA and with decrease d expression of endothelin B receptor (ETB) mRNA. These results sugges t that there is coordinated regulation of genes of the nitric oxide pa thway, which would decrease nitric oxide and cGMP concentration, there by decreasing pulmonary vasodilator activity. There is also coordinate d regulation of genes of the endothelin-1 pathway, which would increas e endothelin-1 concentration and limit ETB receptor activation, thereb y increasing pulmonary vasoconstrictor activity. These alterations in gene expression would increase fetal pulmonary vascular resistance; co ntributing to the development of pulmonary hypertension after birth.