Expression and relationship between endothelin-1 messenger ribonucleic acid (mRNA) and inducible/endothelial nitric oxide synthase mRNA isoforms fromnormal and preeclamptic placentas

Preeclampsia is a mainly vascular disease of pregnancy, probably caused by an imbalance between vasodilator and vasoconstrictor agents that results in generalized vasospasm and poor perfusion in many organs. Among these facto rs, endothelin-1 (ET-1), a potent vasoconstrictor, is highly increased in p reeclamptic women, while nitric oxide (NO), a vasodilator of human utero-pl acental arteries, is reduced in the same patients. The present study was de signed to investigate the interactions between ET-1 and the NO system in th e feto-placental unit; to this purpose we also examined the messenger ribon ucleic acid (mRNA) expression of ET-1, inducible NO synthase (iNOS), and en dothelial NOS (eNOS) in human cultured placental trophoblastic cells obtain ed from preeclamptic (PE) and normotensive (NT) pregnancies. We also studie d whether exogenous ET-1 may affect the expression of iNOS and eNOS in huma n placental trophoblastic cells. Interestingly, by Northern blot analysis m e observed an increased ET-1 mRNA expression level in PE trophoblastic cell s compared to NT trophoblastic cells. Furthermore, exogenous ET-1 (10(-7) m ol/L) was able to up-regulate its own mRNA expression in both NT and PE tro phoblastic cells. iNOS and eNOS mRNA expression was then detected, by semiq uantitative PCR, in both NT and PE trophoblastic cells. PE trophoblastic ce lls expressed lower iNOS mRNA levels compared with NT pregnancies. On the c ontrary, eNOS mRNA expression was higher in PE trophoblastic cells than in NT cells. Moreover, in the presence of ET-1 we observed a decrease in iNOS and an increase in eNOS mRNA expression levels in both NT and PE trophoblas tic cells compared with the respective untreated cells. In conclusion we demonstrate that ET-1 expression is increased in PE cells, whereas iNOS, which represents the main source of NO synthesis. is decreas ed; conversely, eNOS expression is increased. Finally, ET-1 is able to infl uence its own as well as NOS isoform expression in normal and PE trophoblas tic cultured cells. These findings suggest the existence of a functional re lationships between ET(s) and NOS isoforms that could constitute the biolog ical mechanism leading to the reduced placental blood flow and increased re sistance to flow in the fete-maternal circulation, which are characteristic of the pathophysiology of preeclampsia.