EXPRESSION OF THE 3 ENDOTHELIN GENES AND PLASMA-LEVELS OF ENDOTHELIN IN PREECLAMPTIC AND NORMAL GESTATIONS

1. Maternal vasoconstriction and fetal growth retardation are part of the syndrome of pre-eclampsia and are thought to be related to placental insufficiency. There is evidence to suggest that the powerfully vasoactive endothelin peptides might be involved in the pathogenesis. 2. The production of endothelins appears to be regulated mainly by modulation of mRNA levels, and they are thought to exert their effects locally, rather than systemically. Hence, the measurement of endothelin mRNA levels in tissues would be expected to reflect the activity of the endothelin systems. 3. RNAase protection assays, using specific antisense probes capable of distinguishing between the endothelin mRNA isoforms, have been used to examine the expression of the three endothelin genes in placental villous tissue, amniotic membrane and myometrium. Samples were taken from 15 pre-eclamptic women and from 14 women with normal gestations. Myometrium was taken at hysterectomy from five non-pregnant women as an additional control. Plasma concentrations of immunoreactive endothelin [endothelin-1, endothelin-2 and big endothelin (not distinguished)] were measured in samples taken concurrently from uterine vein and peripheral blood during surgery in ten patients. 4. The level of endothelin-1 mRNA in placental villous tissue was significantly higher in pre-eclamptic women (32 weeks gestation) than in control subjects (38 weeks gestation) (1.85 +/- 0.26 versus 0.52 +/- 0.09 arbitrary units, means +/- SEM, P<0.001) and in gravid than in non-gravid myometrium (P<0.001). Endothelin-2 was not expressed in villous tissue, but was expressed in amniotic membrane and myometrium, with relatively little difference between preeclamptic and control groups. Endothelin-3 was expressed at very low levels in all tissues examined. 5. The concentration of immunoreactive endothelin was higher in uterine than in peripheral vein blood in samples which were taken simultaneously (9.0 +/- 1.2 versus 5.6 +/- 0.7 pmol/l, P<0.05). Levels were not significantly different in pre-eclamptic and control groups. 6. Endothelin-1 gene expression is increased in placental villous tissue of pre-eclamptic gestations, possibly contributing to placental vasoconstriction/vascular insufficiency and hence fetal growth retardation in this disease.