Novel Therapeutic Strategies for Preeclampsia

2017-02-08T01:52:33Z (GMT) by Seshini Dinusha Gurusinghe
Preeclampsia remains a leading cause of maternal and perinatal mortality and morbidity worldwide. Whilst the use of anti-hypertensives to control maternal blood pressure and magnesium sulfate for seizure prevention has significantly improved maternal and perinatal outcomes by prolonging pregnancy, delivery of the placenta remains the only definitive treatment for preeclampsia. A therapy that targets the underlying disease itself is very much needed, particularly for women who develop preeclampsia early in gestation. The overall aim of this project was to identify potential therapies or therapeutic strategies that target the underlying disease development process in preeclampsia.

The clinical features of preeclampsia arise from widespread maternal endothelial dysfunction, which in turn is triggered by several vasoactive factors produced by a placenta undergoing ischemia-reperfusion injury. Blocking one or more of the vasoactive factors could significantly ameliorate maternal endothelial dysfunction and thus the clinical features of preeclampsia. Studies have shown that some of the key factors, the agonistic autoantibodies for the angiotensin II type-1 receptor, pro-inflammatory cytokines, and the anti-angiogenic factors, closely interact with each other during disease development. Activin A is another placental-derived factor that contributes to the development of endothelial dysfunction in preeclampsia. While it is well known that pro-inflammatory cytokines can trigger activin A production, the relationship between activin A and the anti-angiogenic factors, soluble fmslike tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), is unknown. Therefore, the first project examined the interactions between activin A and the anti-angiogenic factors, during placental production and the development of endothelial dysfunction, in order to determine whether blocking activin A could disrupt the vasoactive factors and be an effective treatment strategy for preeclampsia. The in vitro studies demonstrated that activin A does not stimulate placental production of the anti-angiogenic factors or vice versa. Furthermore, activin A triggered endothelial dysfunction by increasing endothelial NADPH Oxidase 2 expression and consequently, endothelial oxidative stress, whilst the anti-angiogenic factors did not. Therefore, activin A and the anti-angiogenic factors, sFlt1 and sEng, do not appear to interact with each other either during placental production or the development of endothelial dysfunction. Hence, blocking activin A alone may not rescue maternal endothelial dysfunction sufficiently to completely alleviate the clinical features of preeclampsia.

An alternative treatment strategy would be to alleviate the damage at the two sites of injury in preeclampsia, the maternal endothelium and the placenta. Activation of the Nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor and its downstream anti-oxidant enzymes, such as heme oxygenase-1 was investigated to determine its efficacy in mitigating placental and endothelial dysfunction. Melatonin, an Nrf2 activator, reduced certain hallmarks of endothelial dysfunction in vitro, such as endothelial activation marker expression and endothelial monolayer permeability, but in the placenta, melatonin only reduced oxidative stress and not the production of vasoactive factors. Another Nrf2 activator, resveratrol, reduced all in vitro hallmarks of endothelial function examined, that is endothelial activation marker expression, vasoconstrictor expression and endothelial monolayer permeability. Additionally, resveratrol reduced oxidative stress and production of sFlt1 and activin A by term placental explants. Sulforaphane, one of the most potent Nrf2 activators, also significantly mitigated all the above-mentioned in vitro hallmarks of endothelial function. These experiments also worked towards establishing the sFlt1 and sEng animal model of preeclampsia in our laboratory. Preliminary data from this study suggest that melatonin could potentially mitigate the features of preeclampsia in vivo.

In conclusion, findings from this project demonstrate that inhibition of one vasoactive factor may not be a sufficient treatment strategy for preeclampsia, as some placental-derived vasoactive factors act independently of others during disease development. An alternative treatment strategy is to activate Nrf2 and its downstream anti-oxidant enzymes, which has the potential to improve endothelial function, whilst also reducing placental oxidative stress and production of vasoactive factors. Therefore, Nrf2 activation warrants further investigation as a potential therapeutic strategy for preeclampsia.