Pre-eclampsia (PE) and Gestational Diabetes Mellitus (GDM) are common complications of pregnancy associated with an increased risk of adverse maternal and neonatal outcomes. Both conditions share common pathophysiological features including oxidative stress, inflammation and widespread vascular endothelial dysfunction. It has been proposed that increased insulin resistance may be a common pathogenic link between the two conditions. Women with increased insulin resistance are at an elevated risk of both PE and GDM and GDM is an independent risk factor for the later development of PE.
My recent work has established that endothelial dysfunction in PE is specifically caused by mitochondrial-ROS, rather than ROS generated elsewhere. Intriguingly, there is also emerging evidence of elevated mitochondrial-ROS in GDM. Exciting new data has established a role for mitochondrial damage motifs in provoking inflammation. Furthermore, dysfunctional mitochondria have been shown to activate the NRLP3 inflammasome, a key regulatory nexus mediating obesity-associated insulin resistance. Despite the overwhelming evidence supporting the hypothesis that oxidative damage is involved in the pathophysiology of PE and GDM (more than 800 original scientific articles to date) there is a remarkable disconnect between this supportive literature and a series of large randomised control trials of antioxidant vitamins for the prevention of PE and PE in GDM. My hypothesis is that these nutraceuticals fail to alleviate pathological oxidative damage as they cannot reach the primary source of ROS, the mitochondria, but instead sequester in the cell cytosol.
The aims of this project are to:
define the metabolic, oxidative and inflammatory processes which mediate the immunopathology of PE and GDM
investigate the therapeutic potential of mitochondrial-targeted antioxidants in ameliorating insulin resistance and metainflammation in GDM and PE.
Thus, this program of work will potentially provide an entirely novel therapeutic target for these two important causes of perinatal morbidity and mortality.
