Nitric oxide donor restores lung growth factor and receptor expression in hyperoxia-exposed rat pups.
Exposure of newborn rats to hyperoxia impairs alveolarization. Nitric oxide (NO) may prevent this evolution. Angiogenesis and factors involved in this process, but also other growth factors (GFs) involved in alveolar development, are likely potential therapeutic targets for NO. We studied the effects of the NO donor, [Z]-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)aminio]diazen-1-ium-1, 2-diolate, also termed DETANONOate (D-NO), on hyperoxia-induced changes in key regulatory factors of alveolar development in neonatal rats, and its possible preventive effect on the physiologic consequences of hyperoxia. Newborn rat pups were randomized at birth to hyperoxia (> 95% O2) or room air exposure for 6 or 10 d, while receiving D-NO or its diluent. On Day 6, several GFs and their receptors were studied at pre- and/or post-translational levels. Elastin transcript determination on Day 6, and elastin deposition in tissue and morphometric analysis of the lungs on Day 10, were also performed. Hyperoxia decreased the expression of vascular endothelial growth factor (VEGF) receptor (VEGFR) 2, fibroblast growth factor (FGF)-18, and FGF receptors (FGFRs) FGFR3 and FGFR4, increased mortality, and impaired alveolarization and capillary growth. D-NO treatment of hyperoxia-exposed pups restored the expression level of FGF18 and FGFR4, induced an increase of both VEGF mRNA and protein, enhanced elastin expression, and partially restored elastin deposition in alveolar walls. Although, under the present conditions, D-NO failed to prevent the physiologic consequences of hyperoxia in terms of survival and lung alveolarization, our findings demonstrate molecular effects of NO on GFs involved in alveolar development that may have contributed to the protective effects previously reported for NO.
Institut National de la Santé et de la Recherche Médicale, Université Paris, Faculté de Médecine, Créteil, France.
Emmanuel
E
Lopez
Olivier
O
Boucherat
Marie-Laure
ML
Franco-Montoya
Jacques R
JR
Bourbon
Christophe
C
Delacourt
Pierre-Henri
PH
Jarreau
D000818:Animals; D000831:Animals, Newborn; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018496:Hyperoxia / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D008168:Lung / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D042461:Vascular Endothelial Growth Factor A; C113569:fibroblast growth factor 18; C075278:platelet-derived growth factor A; C467498:vascular endothelial growth factor A, rat; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D005346:Fibroblast Growth Factors; D004549:Elastin; D040301:Vascular Endothelial Growth Factor Receptor-2