Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation
Introduction
Evidence accumulates for almost every physiological system to be closely embedded and regulated by environmental conditions and factors. In pregnancy, similar to the non-pregnant state, the renin-angiotensin II-aldosterone system is a mechanism closely related to salt and water availability [1]. As such, numerous effects beneficial to pregnancy have already been attributed to aldosterone. These include, but are not limited to maternal plasma volume expansion, improved fetal conditions and size, placental growth and lower maternal blood pressure [2], [3], [4], [5], [6], [7], [8]. We recently described that vascular endothelial growth factor (VEGF) alone and in combination with angiotensin II, directs augmented aldosterone production in pregnancy [9], suggesting a physiological survival benefit.
These advantageous characteristics of aldosterone are in marked contrast to its deleterious effects in the non-pregnant state. Organ fibrosis and atherosclerosis are promoted by excess aldosterone [10]. Upon exposure of vessels to aldosterone in models of atherosclerosis, enhanced placental growth factor (PlGF) expression has been observed, mediated by a mineralocorticoid responsive element in the promoter region of plgf [10], [11]. In non-pregnant systemic vasculature, aldosterone-dependent PlGF expression leads to vascular injury, atherosclerosis, plaque formation and its inflammatory response [10], [11]. PlGF is considered to be crucial in pregnancy to initiate and perpetuate placental angiogenesis (reviewed in Ref. [12]). As low levels compromise placental development, it also serves as early marker of pregnancies complicated by pre-eclampsia, a disease of placental origin [13], [14]. The role of environmental conditions on PlGF expression in pregnancy is less clear. Upregulation of angiogenic factors, such as PlGF, in trophoblast seems not to be supported by hypoxia and hypoxia-induced factor-1α [15]. As such, other regulatory pathways must be considered such as glucose availability, which might play a role in this process. While maternal serum levels of PlGF are high in diabetic pregnancies, similar to certain vascular beds such as in the retina, experimental evidence in diabetic rats suggests low PlGF levels in the placenta; thereby a differential regulation between systemic and placental PlGF in response to altered glucose availability [16], [17], [18].
Given the high systemic availability of aldosterone during pregnancy [7], [19], we hypothesized that aldosterone up-regulates growth-adaptive angiogenesis via placental PlGF expression. More specifically, we first aimed to identify trophoblast-derived aldosterone-sensitive PlGF expression; second to explore conditions most likely related to increased responsiveness such as starvation; and third, to investigate the relationship between aldosterone and PlGF in human pregnancy.
Section snippets
Patients
A set of healthy pregnant women selected from the Bernese pregnancy registry at the Department of Obstetrics and Gynecology, University Hospital of Bern, with a complete scheduled sampling of serum and urine were included in the study. Clinical data were prospectively collected including obstetric parameters, ultrasound data, standardized measurement of office blood pressure and pregnancy outcome. Only normotensive, healthy pregnant women were included in the analysis. Visits were at gestation
Clinical data
Demographic data of both the longitudinal Bernese and the complementary first trimester Glasgow cohort of healthy pregnant women with uneventful pregnancies and outcomes are shown in Table 1. The Glasgow cohort, though younger, is characterized by a higher risk profile including a higher BMI and blood pressure and characterized by earlier birth with lower birth weights.
Association between urinary TH-aldosterone and serum PlGF levels
Serum levels of PlGF rose, as expected, along gestation. In normotensive pregnancies, we identified a positive relationship
Discussion
Limited data in clinical conditions outside pregnancy suggest a role for aldosterone in up-regulating PlGF. PlGF is a clinical useful marker of placental angiogenic properties in pregnancy. Given the placental growth properties of aldosterone in pregnancy, such a feature might be of importance for adaptive angiogenesis.
This study demonstrates that in normal human pregnancy, circulating PlGF levels are closely linked to aldosterone availability throughout pregnancy. Obviously, the
Conflict of interest
No conflict of interest exists due to financial or other relationships.
Author contribution
NE, CA, BD, GC, and CG-M performed the research; NE, HDM, MGM and CG-M analyzed the data. All authors wrote, revised and approved the manuscript.
Funding
This research was supported by the Swiss National Foundation (personal grant 32-135596 to MGM and 310030_149958 to CA) and the Swiss National Center of Competence in Research, NCCR TransCure (CA). HDM is supported by an ERA-EDTA Fellowship (LTF 137-2013). CD is supported by grants from the European Union (EU-MASCARA; project reference 278249) and the Chief Scientist Office (reference ETM/196). Additional complementary support was obtained by the clinical research fund of the Department of
Acknowledgments
We are deeply indebted to all pregnant women and their families for participation. We acknowledge the excellent technical support of Heidi Jamin.
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