Natural killer cells in placentation and cancer: Implications for hypertension during pregnancy

Hypertension during pregnancy is the most common medical condition encountered during gestation. Despite this, knowledge of the mechanisms that underlie the disease and the development of new therapies are limited. Hypertension during pregnancy and some forms of cancer confer an increased risk to the development of cardiovascular disease later in life; one mechanism which may link these conditions is the involvement of natural killer (NK) cells. Whilst immunology and immunotherapy are well-developed areas in oncology; the complex mechanisms of the immune system in health and disease at the maternal-fetal interface are less well-defined. Natural killer (NK) cells have emerged as key immune cells involved in physiology and pathology of pregnancy. These small lymphocytes are present in the decidua (the uterine-specific uNK cells) and are distinct from peripheral NK cells. The uNK cell population plays a vital role in mediating trophoblast invasion and affecting decidual vascular remodelling whereas the role of the peripheral NK cell population during pregnancy is less well-defined. This review will give an overview of NK cell biology followed by a discussion of the current evidence for the role of uterine and peripheral NK cells at the maternal-fetal interface in health and disease. Furthermore, examples of NK cell research from cancer biology will be employed to inform future directions of research. By combining this knowledge from oncology where the field of immunotherapy has now matured into clinical trials; it is hopeful that new mechanisms can be elucidated to generate targets for similar therapeutic strategies for women with hypertensive pregnancies where interventions are needed

Preeclampsia: From Inflammation to Immunoregulation

Preeclampsia (PE) affects 5% to 7% of pregnant women each year worldwide, accounts for up to 18% of maternal deaths in the United States each year, and is the number 1 cause of premature births. Preeclampsia is associated with hypertension after the 20th week of gestation with or without proteinuria, in conjunction with fetal growth restriction, maternal endothelial dysfunction, and chronic immune activation. The mechanisms leading to the development of PE are unclear. However, it is thought that shallow trophoblast invasion and insufficient remodeling of uterine spiral arteries result in placental ischemia. Consequently, an immune imbalance characterized by increases in proinflammatory CD4 + T cells and cytokines along with decreases in regulatory T cells and anti-inflammatory cytokines occurs. This imbalance leads to chronic inflammation and ensuing oxidative stress, proinflammatory cytokines, and autoantibodies. Studies performed in our laboratories, using the R educed U terine P erfusion P ressure (RUPP) rat model of placental ischemia, have demonstrated a role for this immune imbalance to mediate PE pathophysiology and identified potential mechanisms of immunoregulation that may be of benefit in the treatment of PE. Therefore, the purpose of this commentary is to review studies demonstrating the positive effects of immunoregulatory factors in the RUPP rat model of PE. Restoration of the immune balance in PE may be a potential strategy for the development of therapeutic interventions that could improve maternal and fetal outcomes associated with this maternal syndrome

Characterization of Mitochondrial Bioenergetics in Preeclampsia

Preeclampsia (PE) is characterized by new onset hypertension during pregnancy and is associated with oxidative stress, placental ischemia, and autoantibodies to the angiotensin II type I receptor (AT1-AA). Mitochondrial (mt) dysfunction in PE and various sources of oxidative stress, such as monocytes, neutrophils, and CD4 + T cells, have been identified as important players in the pathophysiology of PE. We have established the significance of AT1-AA, TNF-α, and CD4 + T cells in causing mitochondrial (mt) dysfunction in renal and placental tissues in pregnant rats. Although the role of mt dysfunction from freshly isolated intact placental mitochondria has been compared in human PE and normally pregnant (NP) controls, variations among preterm PE or term PE have not been compared and mechanisms contributing to mt ROS during PE are unclear. Therefore, we hypothesized PE placentas would exhibit impaired placental mt function, which would be worse in preterm PE patients than in those of later gestational ages. Immediately after delivery, PE and NP patient’s placentas were collected, mt were isolated and mt respiration and ROS were measured. PE patients at either < or >34 weeks gestational age (GA) exhibited elevated blood pressure and decreased placental mt respiration rates (state 3 and maximal). Patients delivering at >34 weeks exhibited decreased Complex IV activity and expression. Placental mtROS was significantly reduced in both PE groups, compared to NP placental mitochondria. Collectively, the study demonstrates that PE mt dysfunction occurs in the placenta, with mtROS being lower than that seen in NP controls. These data indicate why antioxidants, as a potential target or new therapeutic agent, may not be ideal in treating the oxidative stress associated with PE

Tumor necrosis factor alpha (TNF-α) blockade improves natural killer cell (NK) activation, hypertension, and mitochondrial oxidative stress in a preclinical rat model of preeclampsia

The RUPP rat model of Preeclampsia exhibits hypertension (MAP), cytolytic natural killer (cNK) cells, tumor necrosis factor alpha (TNF-α) and mitochondrial Reactive Oxygen Species (mt ROS).  Objective: Does TNF-α blockade with ETAN (Etanercept) decrease cNK cell and mt ROS in RUPP rats. Methods: On gestational day 14, RUPP surgery was performed, ETAN (0.4 mg/kg) was administered on day 18, MAP, blood and tissues collected on 19. Results:MAP, cytolytic NK cells and mt ROS were elevated in RUPP vs. NP and normalized with ETAN. Conclusion: TNF-α blockade lowered blood pressure and improve inflammation and organ function in response to placental ischemia

Tumor necrosis factor alpha (TNF-α) blockade improves natural killer cell (NK) activation, hypertension, and mitochondrial oxidative stress in a preclinical rat model of preeclampsia

Preeclampsia (PE) is associated with placental ischemia, hypertension (MAP), increased cytolytic natural killer (cNK) cells, tumor necrosis factor alpha (TNF-α) and mitochondrial Reactive Oxygen Species (mt ROS). The reduced uterine perfusion pressure (RUPP) rat model of PE, exhibits many characteristics of PE. We have shown that blockade of TNF-α, via etanercept (ETAN), decreases MAP, however, the effect of ETAN on cNK cells and mt ROS is unknown. We hypothesized that ETAN would decrease cNK cell and mt ROS in RUPP rats. Rats were divided into 3 groups: normal pregnant (NP) (n=20), RUPP (n=20), RUPP + ETAN (0.4 mg/kg) (n=20). On gestational day 14, RUPP surgery was performed, and ETAN was administered on day 18, MAP, blood and tissue mitochondria were collected on day 19. MAP was elevated in RUPP vs. NP (118 ± 2 vs. 102± 1 mmHg, p<0.05) which was reduced to 110 ± 2 in RUPP + ETAN (p<0.05). cNK cells were increased in circulation (5.9 ± 1.8 vs. 4.0 ± 1.4 % gated cells), placenta (4.8 ± 1.3 vs. 1.9 ± 0.7 %;), and kidney (3.1 ± 0.5 vs. 0.8 ± 0.5% gated cells; of RUPP vs. NP (p<0.05) and were lowered to 1.5 ± 0.5%, 1.7 ± 0.7%, 0.8 ± 0.5% gated cells in RUPP + ETAN ( p<0.05). Placental and renal mt ROS was reduced with ETAN treatment. TNF-α blockade lowered cNK cells, and mt ROS in placental ischemic rats, which could have contributed to lowered blood pressure observed in response to placental ischemia

Progesterone Induced Blocking Factor Reduces Hypertension and Placental Mitochondrial Dysfunction in Response to sFlt-1 during Pregnancy

Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms-like tyrosine kinase-1 (sFlt-1), and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Progesterone induced blocking factor (PIBF) is a product of progesterone signaling that blocks inflammatory processes and we have previously shown PIBF to lower mean arterial blood pressure (MAP) and sFlt-1 in a rat model of PE. Infusion of sFlt-1 causes hypertension and many characteristics of PE in pregnant rodents, however, its role in causing mt dysfunction is unknown. Therefore, we hypothesize that PIBF will improve mt function and MAP in response to elevated sFlt-1 during pregnancy. We tested our hypothesis by infusing sFlt-1 via miniosmotic pumps in normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg−1·day−1) on gestation days (GD) 13–19 in the presence or absence of PIBF (2.0 µg/mL) injected intraperitoneally on GD 15 and examined mean arterial blood pressure (MAP) and placental mt ROS on GD 19. sFlt-1 increased MAP to 112 + 2 (n = 11) compared to NP rats (98 + 2 mmHg, n = 15, p &lt; 0.05), which was lowered in the presence of sFlt-1 (100 + 1 mmHg, n = 5, p &lt; 0.05). Placental mtATP was reduced in sFlt-1 infused rats versus NP controls, but was improved with PIBF. Placental mtROS was elevated with sFlt-1 compared to NP controls, but was reduced with PIBF. Sera from NP + sFlt-1 increased endothelial cell mtROS, which was attenuated with PIBF. These data demonstrate sFlt-1 induced HTN during pregnancy reduces placental mt function. Importantly, PIBF improved placental mt function and HTN, indicating the efficacy of improved progesterone signaling as potential therapeutics for PE