B2 cells contribute to hypertension and natural killer cell activation possibly via AT1-AA in response to placental ischemia.

Preeclampsia, new onset hypertension during pregnancy, is associated with activated T helper cells (Th) and B cells secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA). The reduced uterine perfusion pressure (RUPP) model of placental ischemia recapitulates these characteristics. We have shown that Th-B cell communication contributes to AT1-AA and symptoms of preeclampsia in the RUPP rat. B2 cells are classical B cells that communicate with Th cells and are then transformed into memory B cells. We hypothesize that B2 cells cause hypertension, natural killer (NK) cell activation, and complement activation during pregnancy through the production of AT1-AA. To test this hypothesis, total splenic B cells and B2 cells were isolated from normal pregnant (NP) or RUPP rats on gestational day (GD)19 and adoptively transferred into GD12 NP rats. A group of recipient rats was treated with a specific inhibitor peptide of AT1-AA. On GD19, mean arterial pressure was measured, tissues were collected, activated NK cells were measured by flow cytometry, and AT1-AA was measured by cardiomyocyte assay. NP recipients of RUPP B cells or RUPP B2 cells had increased mean arterial pressure, AT1-AA, and circulating activated NK cells compared with recipients of NP B cells. Hypertension in NP recipients of RUPP B cells or RUPP B2 was attenuated with AT1-AA blockade. This study demonstrates that B cells and B2 cells from RUPP rats cause hypertension and increased AT1-AA and NK cell activation in response to placental ischemia during pregnancy.NEW & NOTEWORTHY This study demonstrates that placental ischemia-stimulated B2 cells induce hypertension and circulating natural killer cell activation and angiotensin II type 1 receptor production in normal pregnant rats.

The Role of Different Lymphoid Cell Populations in Preeclampsia Pathophysiology.

Preeclampsia (PE), new-onset hypertension during pregnancy, affects up to 10% of pregnancies worldwide. Despite being the leading cause of maternal and fetal morbidity and mortality, PE has no cure beyond the delivery of the fetal-placental unit. Although the exact pathogenesis of PE is unclear, there is a strong correlation between chronic immune activation; intrauterine growth restriction; uterine artery resistance; dysregulation of the renin-angiotensin system. Which contributes to renal dysfunction; and the resulting hypertension during pregnancy. The genesis of PE is thought to begin with insufficient trophoblast invasion leading to reduced spiral artery remodeling, resulting in decreased placental perfusion and thereby causing placental ischemia. The ischemic placenta releases factors that shower the endothelium and contribute to peripheral vasoconstriction and chronic immune activation and oxidative stress. Studies have shown imbalances in proinflammatory and anti-inflammatory cell types in women with PE and in animal models used to examine mediators of a PE phenotype during pregnancy. T cells, B cells, and natural killer cells have all emerged as potential mediators contributing to the production of vasoactive factors, renal and endothelial dysfunction, mitochondrial dysfunction, and hypertension during pregnancy. The chronic immune activation seen in PE leads to a higher risk for other diseases, such as cardiovascular disease, CKD, dementia during the postpartum period, and PE during a subsequent pregnancy. The purpose of this review is to highlight studies demonstrating the role that different lymphoid cell populations play in the pathophysiology of PE. Moreover, we will discuss treatments focused on restoring immune balance or targeting specific immune mediators that may be potential strategies to improve maternal and fetal outcomes associated with PE.

Adoptive transfer of placental ischemia-stimulated natural killer cells causes a preeclampsia-like phenotype in pregnant rats.

PROBLEM: The Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia recapitulates many characteristics of preeclampsia including maternal hypertension, intrauterine growth restriction (IUGR), and increased cytolytic natural killer cells (cNKs). While we have previously shown a 5-fold higher cytotoxicity of RUPP NKs versus normal pregnant NKs, their role in RUPP pathophysiology remains unclear. In this study, we tested the hypotheses that (1) adoptive transfer of RUPP-stimulated NKs will induce maternal hypertension and IUGR in normal pregnant control (Sham) rats and (2) adoptive transfer of Sham NKs will attenuate maternal hypertension and IUGR in RUPP rats. METHOD OF STUDY: On gestation day (GD)14, vehicle or 5 × 106 RUPP NKs were infused i.v. into a subset of Sham rats (Sham+RUPP NK), and vehicle or 5 × 106 Sham NKs were infused i.v. into a subset of RUPP rats (RUPP+Sham NK; n = 12/group). On GD18, Uterine Artery Resistance Index (UARI) was measured. On GD19, mean arterial pressure (MAP) was measured, animals were sacrificed, and blood and tissues were collected for analysis. RESULTS: Adoptive transfer of RUPP NKs into Sham rats resulted in elevated NK activation, UARI, placental oxidative stress, and preproendothelin expression as well as reduced circulating nitrate/nitrite. This led to maternal hypertension and IUGR. RUPP recipients of Sham NKs demonstrated normalized NK activation, sFlt-1, circulating and placental VEGF, and UARI, which led to improved maternal blood pressure and normal fetal growth. CONCLUSION: These data suggest a direct role for cNKs in causing preeclampsia pathophysiology and a role for normal NKs to improve maternal outcomes and IUGR during late gestation.