Effect of Antihypertensive Therapy with Alpha Methyldopa on Levels of Angiogenic Factors in Pregnancies with Hypertensive Disorders

Jauniaux E (2008) Effect of Antihypertensive Therapy with Alpha Methyldopa on Levels of Angiogenic Factors in Pregnancies with Hypertensive Disorders. PLoS ONE 3(7): e2766. doi:10.1371/journal.pone.0002766 Effect of Antihypertensive Therapy with Alpha Methyldopa on Levels of Angiogenic Factors in Pregnancies with Hypertensive Disorders Asma Khalil 0 Shanthi Muttukrishna 0 Kevin Harrington 0 Eric Jauniaux 0 Pisake Lumbiganon, Khon Kaen University, Thailand 0 1 The Homerton University Hospital NHS Trust, Queen Mary and Westfield College, University of London , London , United Kingdom , 2 Academic Department of Obstetrics and Gynaecology, UCL Institute for Women's Health, University College London , London , United Kingdom 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. - Anti-angiogenic and pro-angiogenic factors are known to play an important role in the pathophysiology of pre-eclampsia (PE) [15]. Studies of maternal serum levels of these factors have shown that soluble endoglin (sEng) and soluble fms-like tyrosine kinase 1 (sFlt-1) are elevated in women presenting with PE whereas vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are decreased. Some of these changes can be detected several weeks before the appearance of clinical symptoms of PE [68]. Soluble Flt-1 is a splice variant of VEGF receptor 1 (Flt-1) which is produced by a variety of tissues. Investigation of uterine vein levels of sFlt-1 at cesarean section in pre-eclampsia has suggested a uterine source [9]. The fact that there is a rapid fall in circulating levels of sFlt-1 within 48 hours of delivery is consistent with this concept [4]. Extra-placental sources have also been identified, including endothelial cells, monocytes and peripheral blood mononuclear cells [1012]. Endoglin is a trans-membrane glycoprotein found on cell surfaces highly expressed in endothelial cells and syncytiotrophoblasts [13,14]. sEng is the soluble form of endoglin found in serum. Its level is increased in the circulation of patients with angiogenic tumours, neovascularisation and myeloid malignancies, and of pregnant women [3]. VEGF and P1GF are vascular endothelial growth factors which are key molecules in angiogenesis and vasculogenesis, in particular during embryogenesis [15]. The main source of VEGF and PlGF during pregnancy is the placental trophoblast. VEGF and PlGF are also expressed in many other tissues, including the villous trophoblast [1625]. The most commonly used drug for the treatment of hypertensive disorders in pregnancy in the UK is alpha methyldopa (aMD). Alpha methyldopa acts on alpha-2 adrenoreceptors and is believed to exert its antihypertensive effect primarily in the central nervous system [26,27]. Trophoblast cells also possess alpha-2 adrenoreceptors. The activation of these receptors is thought to modulate intracellular messengers such as cyclic AMP (cAMP) [28,29], so it is possible that aMD also has an effect at this level. Belgore et al [30] have suggested that, in non-pregnant women with essential hypertension, plasma levels of VEGF and sFlt-1 are elevated compared to normotensive controls, and treatment of hypertension significantly reduces the circulating levels of these molecules. The effect of antihypertensive therapy on trophoblast production and/or release of angiogenic factors and thus on their plasma levels in pregnancy is unknown. The aim of this study was to investigate the effect of antihypertensive therapy with alpha methyldopa on maternal serum concentrations and placental production of sFlt-1, sEng, VEGF and PlGF in pregnant women presenting with hypertensive disorders including pre-eclampsia and gestational hypertension. Subjects and samples Serum and placental tissue samples were obtained over an 18 month period from women with singleton pregnancies prospectively recruited in the second and third trimesters of pregnancy at the Homerton University Hospital, London. During this period, approximately 6,000 deliveries took place. Demographic and clinical data including age, body mass index (BMI), parity, blood pressure (BP) and gestational age (GA) were recorded. Gestational age was established on the basis of menstrual date and/or ultrasonographic examination prior to 20 weeks of gestation. All women were followed up until after delivery, and fetal and maternal outcomes were obtained from the womens medical records and labour ward records. Written consent was obtained from each woman after receiving full written information about the research project. This study was approved by the Camden & Islington Community Local Research Ethics Committee and The University College London Hospitals Committee on the Ethics of Human Research. Exclusion criteria included multiple pregnancy, history of hypertension, diabetes, renal disease or immune disorders or women taking medication which could affect blood pressure. The study group in whom serum levels were measured included 51 women presenting with PE, 29 with gestational hypertension and 80 contro (...truncated)