Endothelin and endothelin receptors in human pregnancy and delivery

Abstract

Background: Endothelin-1 (ET-1) is a 21-amino acid peptide, first described by Yanagisawa et al in 1988. It is one of the most potent constrictors of smooth muscle cells identified to date. The facts that ET bears no similarity in its amino acid sequence to the previously known peptides of mammalian origin and the presence of ET in several animal species, including mammals, invertebrates and fish, indicates a long evolutionary history. On the basis of the peptide's constrictive properties and its very high concentration in amniotic fluid and umbilical cord blood, ET was early suggested as a substance of fundamental physiological and/or pathophysiological reproductive importance. The aim of this study was to investigate the concentrations and effects of ET during human pregnancy and delivery.

Materials and methods: Consecutive samples were collected from 40 normal pregnant women and 24 pregnant women with insulin-dependent (type 1) diabetes. Amniotic fluid was collected from 10 normal pregnant women at mid trimester of pregnancy in connection with amniocenteses for genetic purposes. During delivery samples were collected from different compartments (i. e. maternal brachial and uterine veins, retroplacental blood, umbilical artery and vein, amniotic fluid and neonatal urine) of 67 normal pregnant and 35 preeclamptic women. Sampling from the umbilical artery was undertaken both before and after initiation of neonatal breathing. The concentrations of ET-1 and its precursor big ET-1 were measured by radioimmunoassay. The effects of ET on isolated myometrium from 10 normal pregnant women and on intramyometrial and omental arteries from 5 normal pregnant and 5 preeclamptic women were investigated by recording of isometric tension in tissue chambers. The distribution of ET receptor mRNA in the different uterine segments of 8 non-pregnant, 9 normal pregnant and 7 preeclamptic women was studied by a solution hybridization technique.

Results: In healthy women, the serum concentrations of ET-1 and big ET-1 did not change from the 1 8th to the 38th gestational week. Pregnant women with diabetes and preeclampsia showed higher ET levels than healthy pregnant women. In amniotic fluid the ET-1 concentration increased from 1 5th-1 7th gestational weeks to term and exceeded the levels in maternal blood. The ET concentration in the umbilical cord blood was also higher than that in the mother, but there was no difference in ET concentration between the umbilical artery and vein. In the umbilical artery the plasma ET-1 concentration increased considerably at the beginning of neonatal breathing. In preeclampsia the ET-1 concentration in the umbilical vein negatively correlated to birth weight. ET was a potent constrictor of human myometrium and intramyometrial arteries in vitro. The ET receptor gene expression was segmentally differentiated within the uterus, with a proximal-distal decrease in ETA and increase in ETB. During pregnancy the ETA receptor gene in the corpus and the ETB receptor gene in the isthmus were upregulated.

Conclusion: ET-1 might be involved in several physiological and pathophysiological mechanisms in human pregnancy, including the regulation of uterine contractions, closure of the umbilical vessels after birth and development of preeclampsia.