Placental Imbalance of Vasoactive Factors Does Not Affect Pregnancy Outcome in Patients Treated With Cyclosporine A After Transplantation Salvatore Di Paolo, MD, Raffaella Monno, PhD, Giovanni Stallone, MD, Giuseppe Grandaliano, MD, Antonio Schena, MD, Pantaleo Greco, MD, Paolo Volpe, MD, Leonardo Resta, MD, Luigi Selvaggi, MD, F. Paolo Schena, MD, and Loreto Gesualdo, MD ● Endothelin-1 (ET-1) and nitric oxide (NO) have been suggested to have a focal role in the regulation of placental and fetal growth. Cyclosporine A (CsA) has been shown to strongly modulate ET-1 and NO synthesis and thus has the potential to affect fetal growth and maternal state. Eleven CsA-treated female kidney transplant recipients were recruited. Fourteen healthy pregnant women served as controls. Placental expression of ET-1 and tissue factor (TF) was evaluated by in situ hybridization, and NO synthase (NOS) was evaluated by staining with the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH)-diaphorase and in situ hybridization. Kidney transplant recipients showed a marked reduction in NADPH-diaphorase staining, as well as endothelial constitutive NOS (ecNOS) messenger RNA, whereas inducible NOS expression was unchanged. Normal placenta showed a strong positive ET-1 signal along the endothelium of uteroplacental arteries within the basal plate, which increased markedly in decidua of transplant recipients. Thus, transplant recipients showed a remarkable alteration in ET-1/ecNOS balance without alteration in fetal growth or maternal renal function. Next, we explored the state of placental endothelial cell activation downstream from vasoactive factors by evaluating TF gene expression. Transplant recipients did not show modification of TF transcript compared with healthy pregnant women. CsA potently affected the placental ET-1/ecNOS vasoactive balance. Nevertheless, newborns from transplant recipient mothers were appropriate for gestational age, and transplant recipients did not show systemic hypertension or impending renal damage. It is suggested that CsA may blunt the activation of endothelial cells and priming of endothelial-derived substances, which possibly lie downstream from the cited vasoactive agents. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Cyclosporine A (CsA); human placenta; nitric oxide synthase (NOS); endothelin-1 (ET-1); tissue factor (TF); in situ hybridization. C YCLOSPORINE A (CsA) is a widely used immunosuppressive drug that potently af- fects vascular tone through many mediators. Spe- cifically, it has been shown to induce, both in vitro and in vivo, the synthesis and release of endothelin-1 (ET-1), while inhibiting nitric oxide (NO) generation. 1-3 This imbalance between ET-1 and NO systems could help explain such serious clinical side effects observed after long-term CsA treatment as hypertension and nephro- toxicity. 3-5 After the tremendous success of organ trans- plantation, pregnancy has become increasingly frequent among women recipients of solid or- gans, chronically administered CsA. 6-8 Although the incidence of spontaneous abortion within the first trimester, prematurity, and low birth weight is still greater than in the general population, pregnancy outcome among women transplant recipients is successful in most cases, especially with the current immunosuppressive drug dos- age. 6-8 Placental angiogenesis and blood flow are critically dependent on the coordinate interaction of locally produced angiogenic factors and vaso- active agents. 9 In animal models, ET-1 infusion and, conversely, NO synthase (NOS) inhibition, have been shown to induce placental and fetal growth restriction. 10,11 Interestingly, cultured en- dothelial cells of arterial placental blood vessels from preeclamptic women show a dysfunctional mechanism of negative-feedback regulation of ET-1 production by cyclic guanosine monophos- From the Department of Emergency and Organ Trans- plant, Division of Nephrology; II Department of Obstetrics and Gynecology; Department of Pathology and Genetics, University of Bari, Policlinico; the Division of Obstetrics and Gynecology, Hospital Di Venere, Bari; and the Chair of Nephrology, University of Foggia, Foggia, Italy. Received July 11, 2001; accepted in revised form October 26, 2001. Study supported by Centro di Eccellenza Genomica in campo Biomedico e Agrario. Address reprint requests to Loreto Gesualdo, MD, Depart- ment of Emergency and Organ Transplant, Division of Nephrology, University of Bari, Policlinico-Piazza Giulio Cesare, 11-70124 Bari, Italy. E-mail: l.gesualdo@ nephro.uniba.it © 2002 by the National Kidney Foundation, Inc. 0272-6386/02/3904-0014$35.00/0 doi:10.1053/ajkd.2002.31998 American Journal of Kidney Diseases, Vol 39, No 4 (April), 2002: pp 776-783 776