From mother to child--transplacental effect of AT1R-AAin preeclampsia

Preeclampsia is a common hypertensive disorder of pregnancy and a leading cause of maternal and foetal morbidity and mortality worldwide. Preeclampsia requires the presence of the placenta and generally dramatically resolves after placental delivery. The abnormal placentation with failure of trophoblast remodelling of uterine spiral arterioles represents a point where current theories on mechanisms responsible for the condition converge [1]. Various pathways have been proposed to contribute to placental disease. Two major recent concepts, namely, autoimmunity and anti-angiogenesis, have helped us gain new insights into this ‘disease of theories’. Possible mediators leading to impaired angiogenesis in the placenta were recently reviewed [2]. The autoimmunity notion received support with the discovery of autoantibodies directed against the angiotensin (Ang) II Type 1 receptor (AT1R-AA) in the serum of preeclamptic women [3]. AT1R-AA activate the AT1R and induce a cascade of events in various cell types, similar to the actions of Ang II [4]. Increased oxidative stress, increased production of soluble fms-like tyrosine kinase (sFlt-1) in the placenta and initiation of pro-inflammatory and pro-coagulation responses all appear to be key mechanisms resulting from AT1R-AA actions [5]. AT1R-AA were also found in a rodent model for preeclampsia. In that model, the dams of female rats transgenic for the human angiotensinogen gene crossed with male rats transgenic for the human renin gene developed severe (telemetry-measured) hypertension and albuminuria in the latter half of pregnancy, accompanied by glomerular endotheliosis [6]. Thus, many features of the preeclampsia-related maternal syndrome including hypertension, proteinuria and generalized endothelial dysfunction were attributed to circulating AT1R-AA. Preeclamptic AT1R-AA are IgG3 subclass immunoglobulins that target the structures contained in the second extracellular loop of AT1R and induce agonistic responses similar to Ang II despite a different binding site from the natural ligand [3]. Their actions can be neutralized with the corresponding seven-amino-acid peptide sequence or pharmacologic blockade of the AT1R.