The Role of Endogenous Vascular Protection Factors in Preeclampsia

Preeclampsia is the most common of the serious complications of pregnancy. It is caused by a defect in the placenta and is symptomless in the early stages. It is currently only detectable by regular antenatal checks on the mother s blood pressure and urine. In its widest forms, preeclampsia affects about 1 in 10 pregnancies overall and 1 in 50 pregnancies severely. It is potentially life-threatening to mother and baby if allowed to develop and progress undetected. Preeclampsia is curable only by delivery, which puts some babies at risk if they have to be delivered prematurely. Recently, scientists have identified chemicals in the blood (anti-angiogenic factors) that appear to be associated with the onset of preeclampsia. However, it is not known what regulate these anti-angiogenic factors. If we can identify novel mechanisms to inhibit these factors, we could provide preventative treatment.

Preeclampsia (PE) is a systemic endothelial disease defined clinically as hypertension and proteinuria after 20 weeks gestation. PE involves oxidative stress, dysregulation of placental angiogenesis including the release of soluble anti-angiogenic factors that induce systemic endothelial dysfunction. Little attention has been focussed on endogenous vascular protective factors that may inhibit anti-angiogenic factors such as soluble Flt-1 (sFlt-1; a VEGF antagonist) and soluble endoglin (sEng) that are elevated in preeclampsia. This programme will address the central hypothesis that preeclampsia is the result of a perturbation(s) in the vascular protective factors such as the important cytoprotective and anti-inflammatory enzyme, heme oxygenase-1 (HO-1), Thioredoxin reductase-1 (TrxR) and glutathione peroxidase-1 (Gpx), which function to tightly regulate pro- (Vascular endothelial growth factor-A (VEGF) / endothelial nitric oxide (NO) synthase (eNOS) and anti-angiogenic (sFlt-1 / sEng) factors possibly under the control of the phosphoinositide 3-kinase (PI 3-kinase) / Akt pathway. We propose that the HO/TrxR/GpX via PI 3-kinase /Akt pathways are defective in preeclampsia resulting in increased oxidative stress and exacerbated inflammation leading to the aberrant expression of anti-angiogenic factors (sFlt-1 / sEng) in the placenta. This hypothesis will be examined using three experimental systems (i) primary trophoblast and endothelial cell cultures, (ii) a human placental villous explant model and (iii) two transgenic mouse models of preeclampsia. The mechanism by which HO-1 modulates sFlt-1 and sEng expression mediated by pro-inflammatory cytokines (TNF-alpha, IL-1beta, IFN-gamma) and growth factors (VEGF, Ang-II) will be determined by manipulating the PI 3-kinase/PDK-1/Akt, phospholipase C-gamma1 and protein kinase C signal transduction pathways in these systems. This will be achieved by selective RNAi-mediated gene knockdown or over-expression of wild-type and dominant-negative / constitutively active mutants of the appropriate signalling proteins using adenoviral vectors. Understanding the mechanisms that reduce the prevalence of oxidative stress, inflammatory and anti-angiogenic mediators in preeclampsia may prolong pregnancy, prevent premature delivery, and protect the mother post-partum from persistent endothelial cell activation, which increases her predisposition to cardiovascular disease.