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

Abstract

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 (telemetrymeasured) 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. Recent studies on the pathogenesis of preeclampsia focused mainly on the features of the maternal syndrome, as preeclampsia can lead to serious maternal and foetal complications. Agonistic antibody-mediated AT1R stimulation has been demonstrated in severe vascular renal allograft rejection and the passive transfer of human IgG containing AT1R-AA induced vascular lesions similar to the human disease. Furthermore, AT1R-AA led to increased blood pressure in otherwise non-rejecting and normotensive transplanted animals [7]. Investigators from the University of Texas in Houston pursued a similar strategy of passive human IgG transfer. They recently showed that AT1R-AA recovered from the circulation of women with preeclampsia induced preeclampsia-like generalized endothelial dysfunction in pregnant mice. Short duration (5 days) of the passive transfer induced an increase in tail-cuff blood pressure measurements. Links to impaired placental angiogenesis was demonstrated with an increase in sFlt concentrations in the serum of these pregnant mice [8]. sFlt is a shorter splice variant of the functional receptor that lacks the transmembrane domain. The shortened version interferes with angiogenesis and thereby placental development. Together with previous f indings implicating overproduction of plasminogen activator inhibitor-1 and tissue factor in human trophoblast cells, their findings provided further evidence that AT1R-AA may have a causative role in abnormal placentation. Some prototypic features of maternal syndrome in terms of swelling of the endothelial cells (glomerular endotheliosis) were found in the antibody-transferred pregnant mice. However, the mouse model differed from the human disease. For instance, electron microscopic analysis revealed subendothelial deposits of immune complexes. Glomerular immune complex deposition is not common in human preeclampsia [9] and it remains to be determined whether or not the mice developed antibodies against human AT1R-AA IgG used in the transfer experiments. The team from Houston now focused on foetal complications. Intrauterine growth restriction (IUGR) can be