TY - JOUR
T1 - Nitric Oxide (NO) Upregulates NO Synthase Expression in Fetal Intrapulmonary Artery Endothelial Cells
AU - Yuhanna, Ivan S.
AU - MacRitchie, Amy N.
AU - Lantin-Hermoso, Regina L.
AU - Wells, Lieselotte B.
AU - Shaul, Philip W.
PY - 1999
Y1 - 1999
N2 - Endothelium-derived nitric oxide (NO) generated by endothelial NO synthase (eNOS) is critically involved in pulmonary vasodilation during cardiopulmonary transition at birth. Inhaled NO therapy has recently been considered for patients with persistent pulmonary hypertension of the newborn (PPHN). To better understand the mechanisms regulating NO synthesis in the developing pulmonary circulation and the possible ramifications of NO therapy, studies were performed with early passage ovine fetal intrapulmonary artery endothelial cells (PAEC) to determine whether NO directly modulates eNOS expression. To examine the effects of exogenous NO, PAEC were treated with the NO donor spcrmine NONOate or the parent compound spermine. Exogenous NO caused increases in eNOS protein expression and NOS enzymatic activity that were detectable within 16 h of exposure. In contrast, the inhibition of endogenous NO production with nitro-L-arginine-methyl ester (L-NAME) caused a reduction in eNOS protein expression that was evident within 8 h. Paralleling the changes in eNOS protein, eNOS messenger RNA (mRNA) abundance was upregulated by exogenous NO and downregulated by L-NAME, suggesting that NO modulation of eNOS expression involves processes at the level of gene transcription or mRNA stability. Thus, in fetal PAEC there is positive-feedback regulation of eNOS expression by both exogenous and endogenous NO. These findings suggest that difficulties with transient effectiveness or prolonged requirements for NO therapy in certain PPHN patients are not due to declines in eNOS expression. Further, conditions such as fetal hypoxemia that impair PAEC NO production may attenuate eNOS expression through this mechanism, thereby contributing to the pathogenesis of PPHN.
AB - Endothelium-derived nitric oxide (NO) generated by endothelial NO synthase (eNOS) is critically involved in pulmonary vasodilation during cardiopulmonary transition at birth. Inhaled NO therapy has recently been considered for patients with persistent pulmonary hypertension of the newborn (PPHN). To better understand the mechanisms regulating NO synthesis in the developing pulmonary circulation and the possible ramifications of NO therapy, studies were performed with early passage ovine fetal intrapulmonary artery endothelial cells (PAEC) to determine whether NO directly modulates eNOS expression. To examine the effects of exogenous NO, PAEC were treated with the NO donor spcrmine NONOate or the parent compound spermine. Exogenous NO caused increases in eNOS protein expression and NOS enzymatic activity that were detectable within 16 h of exposure. In contrast, the inhibition of endogenous NO production with nitro-L-arginine-methyl ester (L-NAME) caused a reduction in eNOS protein expression that was evident within 8 h. Paralleling the changes in eNOS protein, eNOS messenger RNA (mRNA) abundance was upregulated by exogenous NO and downregulated by L-NAME, suggesting that NO modulation of eNOS expression involves processes at the level of gene transcription or mRNA stability. Thus, in fetal PAEC there is positive-feedback regulation of eNOS expression by both exogenous and endogenous NO. These findings suggest that difficulties with transient effectiveness or prolonged requirements for NO therapy in certain PPHN patients are not due to declines in eNOS expression. Further, conditions such as fetal hypoxemia that impair PAEC NO production may attenuate eNOS expression through this mechanism, thereby contributing to the pathogenesis of PPHN.
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U2 - 10.1165/ajrcmb.21.5.3749
DO - 10.1165/ajrcmb.21.5.3749
M3 - Article
C2 - 10536122
AN - SCOPUS:0033219726
SN - 1044-1549
VL - 21
SP - 629
EP - 636
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 5
ER -