PULMONARY ENDOTHELIAL NO SYNTHASE GENE-EXPRESSION IS DECREASED IN FETAL LAMBS WITH PULMONARY-HYPERTENSION

Nitric oxide (NO), produced by endothelial (e) NO synthase (NOS), is c ritically involved in the cardiopulmonary transition from fetal to neo natal life. We have previously shown that NO-dependent relaxation is a ttenuated in intrapulmonary arteries from fetal lambs with pulmonary h ypertension (PHT) created by prenatal ligation of the ductus arteriosu s. In the present study, we determined whether this is due to altered pulmonary eNOS expression. eNOS and neuronal NOS (nNOS) protein expres sion were assessed in lungs from near-term control lambs and PHT lambs that underwent ductal ligation 10 days earlier. eNOS protein expressi on was decreased 49% in PHT lung. In contrast, nNOS protein abundance was unchanged. NOS enzymatic activity was also diminished in PHT vs. c ontrol lung (60+/-3 vs. 110+/-7 fmol . mg protein-1 . min(-1), respect ively). Paralleling the declines in eNOS protein and NOS enzymatic act ivity, eNOS mRNA abundance was decreased 64% in PHT lung. Thus pulmona ry eNOS gene expression is attenuated in the lamb model of fetal PHT. Because NO modulates both vasodilation and vascular smooth muscle grow th, diminished eNOS expression may contribute to both the abnormal vas oreactivity and the excessive muscularization of the pulmonary circula tion in fetal PHT.