Preeclampsia (PE) affects 5–7% of all pregnancies in the United States and is the leading cause of maternal and prenatal morbidity. PE is associated with hypertension after week 20 of gestation, decreased renal function and small-for-gestational-age babies. Women with PE exhibit chronic inflammation and production of autoantibodies. It is hypothesized that during PE, placental ischaemia occurs as a result of shallow trophoblast invasion which is associated with an immune imbalance where pro-inflammatory CD4⁺ T-cells are increased and T regulatory cells (Tregs) are decreased. This imbalance leads to chronic inflammation characterized by oxidative stress, pro-inflammatory cytokines and autoantibodies. Studies conducted in our laboratory have demonstrated the importance of this immune imbalance in causing hypertension in response to placental ischaemia in pregnant rats. These studies confirm that increased CD4⁺ T-cells and decreased Tregs during pregnancy leads to elevated inflammatory cytokines, endothelin (ET-1), reactive oxygen species (ROS) and agonistic autoantibodies to the angiotensin II (Ang II), type 1 receptor (AT1-AA). All of these factors taken together play an important role in increasing the blood pressure during pregnancy. Specifically, this review focuses on the decrease in Tregs, and their associated regulatory cytokine interleukin (IL)-10, which is seen in response to placental ischaemia during pregnancy. This study will also examine the effect of regulatory immune cell repopulation on the pathophysiology of PE. These studies show that restoring the balance of the immune system through increasing Tregs, either by adoptive transfer or by infusing IL-10, reduces the blood pressure and pathophysiology associated with placental ischaemia in pregnant rats.

Preeclampsia is associated with autoimmune cells T_H17, secreting interleukin-17, autoantibodies activating the angiotensin II type I receptor (AT1-AA), and placental oxidative stress (ROS). The objective of our study was to determine whether chronic IL-17 increases blood pressure by stimulating ROS and AT1-AAs during pregnancy. To answer this question four groups of rats were examined: normal pregnant (NP, n = 20), NP+IL-17 ( n = 12), NP+tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine- N-oxyl) ( n = 7) (a superoxide dismutase mimetic that scavenges ROS), and NP+IL-17+tempol ( n = 11). IL-17 (150 pg/day) was infused into NP rats while tempol was administered via the drinking water ad libitum. On day 19 blood pressure (MAP) was recorded, and plasma, urine, and tissue were collected for isolation of ROS detected by chemilluminescent technique. Urinary isoprostane was measured by ELISA. AT1-AAs were determined via cardiomyocyte assay and expressed as beats per minute. MAP increased from 98 ± 3 mmHg in NP to 123 ± 3 mmHg in IL-17-infused NP rats. Urinary isoprostane increased from 1,029 ± 1 in NP to 3,526 ± 2 pg·mg⁻¹·day⁻¹ in IL-17-infused rats ( P < 0.05). Placental ROS was 436 ± 4 RLU·ml⁻¹·min⁻¹ ( n = 4) in NP and 702 ± 5 ( n = 5) RLU·ml⁻¹·min⁻¹ in IL-17-treated rats. Importantly, AT1-AA increased from 0.41 ± 0.05 beats/min in NP rats ( n = 8) to 18.4 ± 1 beats/min in IL-17 rats ( n = 12). Administration of tempol attenuated the hypertension (101 ± 3 mmHg) ROS (459 ± 5 RLU·ml⁻¹·min⁻¹) and blunted AT1-AAs (7.3 ± 0.6 beats/min) in NP+IL-17+tempol-treated rats. Additionally, AT1 receptor blockade inhibited IL-17-induced hypertension and placental oxidative stress. MAP was 105 ± 5 mmHg and ROS was 418 ± 5 RLU·ml⁻¹·min⁻¹ in NP+IL 17-treated with losartan. These data indicate that IL-17 causes placental oxidative stress, which serves as stimulus modulating AT1-AAs that may play an important role in mediating IL-17-induced hypertension during pregnancy.

Preeclampsia (PE) is a pregnancy-specific syndrome and one of the leading causes of preterm birth, neonatal and maternal morbidity and mortality. This disease is characterized by new onset hypertension usually in the third trimester of pregnancy and is sometimes associated with proteinuria, although proteinuria is not a requirement for the diagnosis of PE. In developing countries, women have a higher risk of death due to PE than more affluent countries and one of the most frequent causes of death is high blood pressure and stroke. Although PE only affects approximately 2%–8% of pregnancies worldwide it is associated with severe complications such as eclampsia, hemorrhagic stroke, hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), renal failure and pulmonary edema. Importantly, there is no “cure” for the disease except for early delivery of the baby and placenta, leaving PE a health care risk for babies born from PE moms. In addition, PE is linked to the development of cardiovascular disease and stroke in women after reproductive age, leaving PE a risk factor for long-term health in women. This review will highlight factors implicated in the pathophysiology of PE that may contribute to long-term effects in women with preeclamptic pregnancies.

We have shown that hypertension in response to chronic placental ischemia is associated with elevated inflammatory cytokines and CD4 ⁺ T cells. However, it is unknown whether these cells play an important role in mediating hypertension in response to placental ischemia. Therefore, we hypothesize that reduced uterine perfusion pressure (RUPP)–induced CD4 ⁺ T cells increase blood pressure during pregnancy. To answer this question, CD4 ⁺ T cells were isolated from spleens at day 19 of gestation from control normal pregnant (NP) and pregnant RUPP rats, cultured, and adjusted to 10 ⁶ cells per 100 μL of saline for intraperitoneal injection into NP rats at day 13 of gestation. On day 18, in the experimental groups of rats, arterial catheters were inserted, and on day 19 mean arterial pressure was analyzed. Inflammatory cytokines and antiangiogenic factor soluble fms-like tyrosine kinase 1 were determined via ELISA. Mean arterial pressure increased from 104±2 mm Hg in NP rats to 124±2 mm Hg in RUPP rats ( P <0.001) and to 118±1 mm Hg in rats receiving RUPP CD4 ⁺ T cells ( P <0.001). Circulating tumor necrosis factor-α and soluble fms-like tyrosine kinase 1 were elevated in recipients of RUPP CD4 ⁺ T cells to levels similar to control RUPP rats. In contrast, virgin rats injected with NP or RUPP CD4 ⁺ T cells exhibited no blood pressure changes compared with control virgin rats. Importantly, mean arterial pressure did not change in recipients of NP CD4 ⁺ T cells (109±3 mm Hg). These data support the hypothesis that RUPP-induced CD4 ⁺ T cells play an important role in the pathophysiology of hypertension in response to placental ischemia.