A role for noradrenaline in pre‐eclampsia: towards a unifying hypothesis for the pathophysiology

Abstract

Objective To compare plasma catecholamine (noradrenaline and adrenaline) levels in pre-eclamptic to normotensive pregnancy, and to study the activity of synthetic enzymes for catecholamines in placental and trophoblastic cell cultures. We postulated that catecholamines might be an important signal secreted by the fetoplacental unit in pre-eclampsia. MethodsWe recruited 12 women with pre-eclampsia and 12 pregnant women with nonproteinuric hypertension undergoing delivery by caesarean section, 23 normotensive women undergoing elective caesarean section at term, and 26 normotensive primigravid women with ongoing pregnancies at gestations equivalent to those women with pre-eclampsia. We measured venous blood concentrations of catecholamines. Following delivery, we studied tyrosine hydroxylase (the rate limiting enzyme for catecholamine synthesis) activity in placental tissue of these women as well as from four eclamptic women not in the observer study. We used Northern blot analysis to quantify mRNA for tyrosine hydroxylase and dopamine-P-hydroxylase (D-P-H, a non-rate-limiting synthetic enzyme for catecholamine) in placental tissue, as well as in trophoblast cells in primary culture and trophoblast cell lines.Results Venous blood concentrations of noradrenaline were significantly higher in pre-eclamptic women compared with normotensive women. Tyrosine hydroxylase activity was greater in placental tissue from pre-eclamptic and eclamptic compared with normotensive pregnancies, as were mRNA levels for this enzyme. The mRNA levels for the non-rate-limiting D-P-H in women with pre-eclampsia were similar to those in normotensive pregnancies. First trimester trophoblast cells in primary culture and trophoblast cell lines transcript mRNA for tyrosine hydroxylase and D-P-H. ConclusionsTrophoblasts have the capacity to secrete catecholamines, and we found increased activity of the rate-limiting synthetic enzyme in placental tissue from pre-eclamptic pregnancies. We postulate that the higher levels of catecholamines we found in the plasma of women with pre-eclampsia might be of placental origin. We hypothesise that in pre-eclampsia ischaemic trophoblast tissue secretes catecholamines as a physiological signal to increase maternal blood flow to the fetoplacental unit, which itself is spared the vasoconstrictor effects of catecholamines (placental vessels are known to be unresponsive to catecholamines). However, since the basic pathology-defective trophoblast invasion-is not corrected, the increased blood flow fails to resolve the ischaemia, and the secretion of catecholamines is therefore sustained or even enhanced. Noradrenaline is known to cause lipolysis. This results in breakdown of triglycerides to free fatty acids, which are oxidized to lipid peroxides. The latter are cytotoxic and cause widespread endothelial cell damage and dysfunction, culminating in the clinical syndrome of pre-eclampsia.

Maternal Preeclampsia Predicts Elevated Blood Pressure in 12-Year-Old Children: Evaluation by Ambulatory Blood Pressure Monitoring

“…In previous studies, plasma catecholamine concentrations have been found to be increased in PRE pregnant women (4,25,26), and increased catecholamine secretion was supposed to be of placental origin (26). In our study, the PRE children tended to have slightly higher circulating E levels than the non-PRE children.…”

Does hypertensive disorder of pregnancy predict offspring blood pressure at 21 years? Evidence from a birth cohort study

“…In previous studies, plasma catecholamine concentrations have been found to be increased in pregnant women with preeclampsia. [19][20][21] It was also noted that children exposed to preeclampsia have slightly higher circulating epinephrine levels than children born to normal mothers. 5 Recently, it has been found that young offspring of mothers with preeclampsia display marked vascular dysfunction in the systemic circulations and that this endothelial defect in the systemic circulation may contribute to the increased risk of arterial hypertension in the offspring.…”

Psychosocial Stress Related to the Loss of a Close Relative the Year Before or During Pregnancy and Risk of Preeclampsia

“…1,2 Despite its relatively well-described pathophysiology, decades of intensive research, and its important consequences, the actual causes and the means to prevent the disease are still quite unknown. 1,2 Preeclampsia has been characterized as "a state of sympathetic overactivity," 3,4 which could be present already in the preclinical phase of the disease. 5 Psychosocial stress induces sympathetic arousal, activates the hypothalamic-pituitaryadrenal axis, and may thus promote endothelial dysfunction, 6 proinflammatory activity, 7,8 and blood pressure elevations.…”