Endothelin and nitric oxide in the fetoplacental circulation

Background: Normal fetal growth and development depend on a satisfactory uteroplacental and fetoplacental blood flow. This will ensure an adequate gaseous exchange and nutritional supply to the fetus. The importance of maintaining an adequate blood flow in both these circulations is emphasized in disease states, such as preeclampsia and intrauterine growth retardation, where blood flow is compromised and perinatal outcome impaired. The control of the blood flow within the fetoplacental circulation has been much studied but is not fully understood. The general aim of the thesis was to study the physiology of placental arteries with special regard to endothelin and nitric oxide, two of the most potent vasoactive agents known, and furthermore to investigate the role of endothelin and the cytokine M-CSF in amniotic fluid.

Methods: Placentas from normal pregnancies were collected, arteries were dissected and mounted in organ baths where the tension was recorded isometrically with a Grass FT03C force-displacement transducer and registered on a polygraph. Agonist and antagonists were added and contraction and relaxation of the vessels were registered. The amount of cGMP in the vessels was analysed by immunoassay. The distribution of investigated substances in the vessels was analyzed by immunohistochemistry. Primary cultures of human amniocytes were established and their ability to produce endothelin- 1 and M-CSF in response to interleukin-1 were analysed by immunoassay. Amniotic fluid was collected from pregnant women with suspect lUGR in conjunction with karyotyping and endothelin-1 and M-CSF were analysed by immunoassay.

Results and conclusion: We found that ETA- and ETB-receptors are expressed in the vascular wall of placental arteries, and that endothelin-1 contracts human placental arteries through both ETA- and ETBreceptors. We also found that endothelial nitric oxide synthase is expressed in placental arteries, and that nitric oxide strongly affects contraction tone in human placental arteries. Nitric oxide induced relaxation of human placental arteries was mediated partly by cGMP and partly through direct activation of potassium channels. Endothelin- 1 and M-CSF are colocalized in human amniotic membrane cells and secreted into amniotic fluid. In summary, our data support an important role for ETA and NO in the regulation of vascular tone in the fetoplacental circulation.

List of scientific papers

I. Sand AE, Ostlund E, Andersson E, Fried G (1998). "Endothelin-induced contractions in placental arteries is mediated by both ETA- and ETB-receptors. " Acta Physiol Scand 163(3): 227-34
https://pubmed.ncbi.nlm.nih.gov/9715734

II. Sand AE, Andersson E, Fried G (2002). "Effects of nitric oxide donors and inhibitors of nitric oxide signalling on endothelin- and serotonin-induced contractions in human placental arteries." Acta Physiol Scand 174(3): 217-23
https://pubmed.ncbi.nlm.nih.gov/11906320

III. Sand AE, Andersson E, Fried G (2004). "Nitric oxide donors mediate vasodilation in human placental arteries partly through a direct effect on potassium channels." Placenta (Submitted)

IV. Fried G, Sand A, Ostlund E, Andersson E, Bystrom B, Stabi B (2003). "Endothelin-1 and macrophage colony-stimulating factor are co-localized in human amnion membrane cells and secreted into amniotic fluid. " Mol Hum Reprod 9(11): 719-24
https://pubmed.ncbi.nlm.nih.gov/14561814