Project I: Inflammation, HTN, and Long-term Effects on Maternal Well Being

Hypertension during pregnancy, such as preeclampsia (PE), is an important cause of maternal and fetal death in the U.S. Women with PE are affected with neurological compromise, immune system dysregulation, and increased agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA). Circulating CD4+ T cells and inflammatory cytokines, and the AT1-AA are all associated with hypertension and increased cerebral perfusion pressure resulting in impaired cerebral autoregulation and increased blood-brain barrier (BBB) permeability. Reports of increased anxiety, depression and cognitive impairment have been made in women with PE. Experimental AT1 receptor studies suggest a possible role between the AT1-AA during pregnancy and postpartum (PP) psychological and neurological complications. Therefore, the central hypothesis is that during hypertensive disorders of pregnancy, the increase in immune cells (CD4+ T cells, B cells, and macrophages) leads to increased AT1-AA-induced systemic inflammation stimulating an impairment in cerebral hemodynamics, ultimately leading to increased BBB permeability, which is associated with anxiety, depression and cognitive impairment during pregnancy and the PP period. Recent data from animal studies report that increased maternal AT1-AA levels are associated with increased levels of AT1-AA in offspring. As such, we will examine infant development among male and female children born to women in this study. Specific Aim 1 To test the hypothesis that increases in CD4+ T cells, B cell secreting AT1-AA, and macrophages positively correlate with cognition or mood changes during pregnancy and the PP period among women with PE. We will use results from an assemblage of validated questionnaires designed to assess anxiety, depression and cognitive impairment during pregnancy and the PP to determine if psychological results correlate with immunological changes. Specific Aim 2. To test the hypothesis that cerebral autoregulation impairment and BBB damage in women with PE is due to increased levels of the AT1-AA, IL-17, and TNFα. An association between AT1-AA levels, circulating inflammatory and neurovascular markers, cerebral autoregulation (measured via transcranial doppler) and in vitro BBB assays will be determined. Specific Aim 3. To test the hypothesis that maternal AT1-AA impacts infant development and to investigate if these effects are dependent on sex differences. Infant development will be measured and associated with sex differences, placental ACE-2 and levels of the AT1-AA.