Effect of antihypertensive therapy with alpha methyldopa on levels of angiogenic factors in pregnancies with hypertensive disorders

Abstract

Background: Antihypertensive drugs are believed to lower blood pressure in pre-eclampsia by direct or central vasodilatory mechanisms. However, they could also act by decreasing production of anti-angiogenic proteins involved in the pathophysiology of hypertension and proteinuria in pre-eclampsia (PE). The aim of our study was to evaluate the impact of antihypertensive therapy with alpha methyldopa on maternal circulating levels and placental production of soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng), vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in hypertensive disorders of pregnancy.

Methodology/principal findings: In a study conducted at University College Hospital and the Homerton University Hospital in London, we recruited 51 women with PE, 29 with gestational hypertension (GH), and 80 matched normotensive controls. Eight (16%) of the women with PE had severe disease. Placental samples were obtained from a further 48 women (14 PE, 10 GH and 24 matched controls). Serum levels of angiogenic factors were measured before and 24-48 hours after commencing antihypertensive therapy with alpha methyldopa for clinical indications. The same parameters were measured in placental extracts. In both PE (P<0.0001) and GH (P<0.05), serum sFlt-1 was increased and PlGF reduced at all gestations (P<0.001) compared to controls. Serum sEng levels were also increased in PE. Placental concentration of sFlt-1 and sEng was significantly higher in women with PE compared to controls and women with GH (P<0.0001). The concentration of PlGF was significantly lower in the placental tissue of women with PE compared to GH (P = 0.008). Antihypertensive treatment was associated with a significant fall in serum and placental content of sFlt1 and sEng in PE only.

Conclusions: Our data suggest that alpha methyldopa may have a specific effect on placental and/or endothelial cell function in pre-eclampsia patients, altering angiogenic proteins.

Figure 1. Women recruited to the study.

Flow diagrams of women recruited to the serum (a) and placental (b) arms of the study respectively.

Figure 2. Serum concentrations of angiogenic factors in normotensive women, women with pre-eclampsia and women with gestational hypertension who received methyldopa.

Mean serum sFlt-1 (a), PlGF (b) and sEng (c) concentrations in normotensives (controls), women with pre-eclampsia and women with gestational hypertension according to gestational age (GA) interval [early onset <34 weeks (41 controls, 28 PE, 13 GH) and late onset ≥34 weeks (39 controls, 23 PE, 16 GH)]. Error bars represent standard errors. Comparison of controls and cases (with PE or GH) was performed after logarithmic transformation. Levels before and after alpha methyldopa therapy are shown for women with pre-eclampsia and women with gestational hypertension. The levels in the three groups were compared using ANOVA with Bonferroni Dunn's posthoc tests. The levels before and after antihypertensive therapy are compared using the paired t test. ****P<0.0001, ***P<0.001, **P<0.01, *P<0.05. P values are shown only for differences which are statistically significant.

Figure 3. Maternal serum concentrations of angiogenic factors in early and late onset PE, and in mild and severe PE.

Mean maternal serum concentrations of sFlt-1 (a), PlGF (b) and soluble endoglin (c) in women with early onset and late onset PE, and in women with mild and severe PE. Error bars represent standard errors. Early onset were compared with late onset, and mild with severe PE after logarithmic transformation using unpaired t test.

Figure 4. Placental concentrations of angiogenic factors in normotensive women, women with pre-eclampsia and gestational hypertension.

Concentrations of sFlt-1(a), PlGF (b), soluble endoglin (c) and VEGF (d) (expressed per mg protein) in placental tissue from normotensive (controls, n = 24, pre-eclampsia (PE, n = 14) and gestational hypertension (HT, n = 10 pregnancies. Error bars represent standard errors. Comparison of controls and cases (with PE or GH) was performed after logarithmic transformation. The mean gestational ages (days) for the three groups were (mean±SD): controls 242±16; pre-eclampsia 238±13; gestational hypertension 243±20.