l -Arginine Depletion in Preeclampsia Orients Nitric Oxide Synthase Toward Oxidant Species

Abstract

Abstract-Less nitric oxide (NO)-dependent vasodilation and excess formation of reactive oxygen species could explain poor placenta perfusion in preeclampsia, but the pathways involved are unknown. We tested the hypothesis that reduced NO activity and increased oxidative stress in preeclamptic placenta is related to a low bioavailability of L-arginine. Placental endothelial NO synthase (ecNOS) expression (by immunoperoxidase) and activity (by diaphorase and [ 3 H]L-citrulline formation) were comparable in normotensive pregnancy and in preeclampsia, whereas nitrotyrosine staining, a marker of peroxynitrite, was stronger in preeclamptic villi, confirming previously reported data. Oxidative tissue damage was documented in preeclamptic villi by strong 4-hydroxynonenal-lysine staining (by immunoperoxidase), which closely colocalized with nitrotyrosine. Concentration of the NO precursor L-arginine (by HPLC) in umbilical blood and in villous tissue was lower in preeclampsia than in normotensive pregnancy. This was not caused by a defective L-arginine transport, because gene expression of the CAT-1, 4F2hc, and LAT-1 cationic amino acid transporters (by real-time reverse-transcription polymerase chain reaction [RT-PCR]) was normal. Instead, gene expression (by real-time RT-PCR) and protein tissue content (by immunoperoxidase and Western blot) of arginase II-the enzyme that degrades arginine to ornithine-were higher in preeclamptic villi than in normotensive pregnancy. These results provide a biochemical explanation for defective NO activity and increased oxidative stress in preeclamptic placenta. In normal placenta, adequate concentration of L-arginine orients ecNOS toward NO. In preeclampsia, a lower than normal L-arginine concentration caused by arginase II overexpression redirects ecNOS toward peroxynitrite. Key Words: arginine Ⅲ nitric oxide synthase Ⅲ nitrites Ⅲ oxidative stress Ⅲ preeclampsia I n the past few years, evidence has accumulated suggesting that nitric oxide (NO), a potent endothelial-derived vasodilator, might be implicated in gestational vasodilation. 1,2 NO is synthesized from the amino acid L-arginine by a family of enzymes, the NO synthases (NOS). 3 While human placenta does not form inducible NOS (iNOS) or neuronal NOS (nNOS) mRNAs and proteins, 1 the endothelial isoform of NOS (ecNOS) is actually detectable in healthy placenta and is localized to the endothelium of the umbilical cord, chorionic plate, and stem villous vessels. 1 Conceivably, locally formed NO serves to maintain low vascular resistance besides attenuating the action of vasoconstrictors. 1 Besides, ecNOS is localized in villous cytotrophoblasts, 1,4 the specialized epithelial cells that aggregate into cell columns and invade the uterine interstitium and vasculature, anchoring the fetus to the mother and establishing blood flow to the placenta. 5 By virtue of its unique angiogenic/vasculogenic properties, 6,7 locally generated NO may be instrumental to promote this cytotrophoblast endovascular invasion that is an essential feature o...

Recent Progress Toward the Understanding of the Pathophysiology of Hypertension During Preeclampsia

“…Much of the uncertainty in this area of research originates from the difficulty in directly assessing the activity of the NO system in the clinical setting. Recently, Noris et al 34 suggested that L-arginine depletion, caused by arginase II overexpression, may orient NO synthase toward oxidant species in placenta in preeclampsia. In addition, McCord and colleagues 35 reported that a relative deficiency of arginine in peripheral blood mononuclear cells may favor superoxide and peroxynitrite production and contribute to oxidative and nitrosative stress in preeclampsia.…”

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“…At least 8 -10 fields per section were examined. The final score per section was calculated as a weighted mean (38).…”

New Aspects in the Pathophysiology of Preeclampsia

“…Several groups have reported alterations in cytokines/growth factors/chemicals such as TNF-␣, IL-6, IL-1␣, IL-1␤, Fas ligand, oxidized lipid products, neurokinin-B, and asymmetric dimethyl arginine (ADMA) that are released by the placenta and/or other maternal sources in preeclampsia (18 -22). Recently, a lower-than-normal L-arginine concentration that is caused by arginase II overexpression and that may redirect placental endothelial nitric oxide (NO) synthase toward peroxynitrite was described in preeclampsia (23).…”