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.

The role of tumor necrosis factor in triggering activation of natural killer cell, multi-organ mitochondrial dysfunction and hypertension during pregnancy.

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy associated with chronic inflammation, mitochondrial (mt) dysfunction and fetal demise. Natural Killer cells (NK cells) are critical for the innate immune response against tumors or infection by disrupting cellular mt function and causing cell death. Although NK cells can be stimulated by Tumor necrosis factor alpha (TNF-α), we don't know the role of TNF-α on NK cell mediated mt dysfunction during PE. Our objective was to determine if mechanisms of TNF-α induced hypertension included activation of NK cells and multi-organ mt dysfunction during pregnancy. Pregnant rats were divided into 2 groups: normal pregnant (NP) (n = 18) and NP + TNF-α (n = 18). On gestational day 14, TNF-α (50 ng/ml) was infused via mini-osmotic pump and on day 18, carotid artery catheters were inserted. Blood pressure (MAP) and samples were collected on day 19. TNF-α increased MAP (109 ±â€¯2 vs 100 ±â€¯2, p < 0.05), circulating cytolytic NK cells (0.771 ±â€¯0.328 vs.0.008 ±â€¯0.003% gated, <0.05) and fetal reabsorptions compared to NP rats. Moreover, TNF-α caused mtROS in the placenta (12976 ±â€¯7038 vs 176.9 ±â€¯68.04% fold, p < 0.05) and in the kidney (2191 ±â€¯1027 vs 816 ±â€¯454.7% fold, p < 0.05) compared to NP rats. TNF-α induced hypertension is associated fetal demise, activation of NK cells and multi-organ mt dysfunction which could be mechanisms for fetal demise and hypertension. Understanding of the mechanisms by which TNF-α causes pathology is important for the use of anti-TNF-α therapeutic agents in pregnancies complicated by PE.

Angiotensin II type 1 autoantibody induced hypertension during pregnancy is associated with renal endothelial dysfunction.

BACKGROUND: Previous investigations suggested that agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) might mediate a hypertensive response through dysregulation of the endothelin-1 system. AT1-AA induced hypertension was attenuated by the AT1 receptor and/or endothelin-1 type A receptor antagonists. OBJECTIVES: This study was undertaken to determine if AT1-AA induced hypertension was associated with renal endothelial dysfunction. METHODS: We compared the vascular reactivity of renal interlobar arteries from normal pregnant control rats and AT1-AA long-term infused pregnant rats in the presence and absence of endothelin type A (ET(A)) receptor antagonism. Renal endothelial function was tested using isolated renal interlobar arteries in a pressure myograph, which were exposed to acetylcholine or sodium nitroprusside. RESULTS: Vasodilatory responses to the endothelial-dependent agonist acetylcholine were impaired in AT1-AA rats (74 [10]%) compared with normal pregnant controls (95 [5]%, P < 0.05). In the presence of ET(A) receptor antagonism, no differences were observed between controls or the AT1-AA treated group with regard to endothelial-dependent (acetylcholine) relaxation. CONCLUSION: AT1-AA induced hypertension during pregnancy was associated with disparate renal endothelial responses to acetylcholine. The difference in renal vascular responses between AT1-AA and normal pregnant rats was abolished by ET(A) receptor blockade.

Changes in cardiac structure in hypertension produced by placental ischemia in pregnant rats: effect of tumor necrosis factor blockade.

OBJECTIVES: Chronic reduction of uteroplacental perfusion pressure (RUPP) in pregnant rats leads to placental ischemia, maternal endothelial cell dysfunction, hypertension and elevated levels of tumor necrosis factor-alpha (TNF-α). In this study we investigated the hypothesis that placental ischemia in pregnant rat, a model of preeclampsia, stimulates cardiac hypertrophy and fibrosis via a TNF-α-dependent mechanism. METHODS: Normal pregnant Sprague-Dawley rats and RUPP rats were evaluated on day 19 of gestation. To test the role of TNF-α in mediating change in the RUPP rat heart, a TNF-α inhibitor, etanercept, was administered on day 18 of gestation at a dose of 0.8 mg/kg, s.c. RESULTS: In comparison to normal pregnant rats, RUPP animals display enlarged cardiomyocytes, microvascular rarefaction, fibrosis, apoptosis as well as increased expression of markers of heart hypertrophy and fibrosis. Etanercept (E) treatment prevented enlargement of cardiomyocytes, fibrosis and apoptosis and this was accompanied by significantly lowered blood pressure in RUPP rats. Etanercept treatment lowered expression of mRNA for brain natriuretic peptide, a marker of cardiac hypertrophy. It also heightened expression of endothelial nitric oxide synthase and its phosphorylation as well as oxytocin receptor identified in cardiac microvessels. TNF-α inhibition prevented microvascular rarefaction in the heart as indicated by augmented CD31, a marker of angiogenesis. CONCLUSIONS: These results suggest that RUPP leads to microvascular rarefaction in the heart, exaggerated cardiomyocyte size, apoptosis, fibrosis, and the alteration of cardiac gene expression that are modulated by the inflammatory cytokine TNFα.

Tumor necrosis factor-alpha antagonist etanercept decreases blood pressure and protects the kidney in a mouse model of systemic lupus erythematosus.

Chronic inflammation has been implicated in the pathology of hypertension; however, the role for specific cytokines remains unclear. We tested whether tumor necrosis factor-α blockade with etanercept (Etan) reduces mean arterial pressure in a female mouse model of systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disorder with prevalent hypertension. Thirty-week-old SLE (NZBWF1) and control mice (NZW/LacJ) received Etan (0.8 mg/kg SC weekly) for 4 weeks or vehicle. Mean arterial pressure (in millimeters of mercury) was increased in SLE mice (150±5 versus 113±5 in controls; P<0.05) and was lower in Etan-treated SLE mice (132±3) but not controls (117±5). Albuminuria (in micrograms per milligram of creatinine) was elevated in SLE mice (28 742±9032 versus 1075±883; P<0.05) and was lower in Etan-treated SLE mice (8154±3899) but not control animals (783±226). Glomerulosclerosis (in percentage of glomeruli) was evident in SLE mice (2.5±1.6 versus 0.0±0.0 in controls; P<0.05) and was ameliorated in Etan-treated SLE mice (0.1±0.1). Renal cortex CD68(+) cell staining (in percentage of area) was elevated in SLE mice (4.75±0.80 versus 0.79±0.12 in controls; P<0.05) and was lower in Etan-treated SLE mice (2.28±0.32) but not controls (1.43±0.25). Renal cortex NADPH oxidase activity (relative light units per milligram of protein) was higher in SLE mice compared with controls (10 718±1276 versus 7584±229; P<0.05) and lowered in Etan-treated SLE mice (6645±490). Renal cortex nuclear factor κB (phosphorylated and nonphosphorylated) was increased in SLE mice compared with controls and lower in Etan-treated SLE mice. These data suggest that TNF-α mechanistically contributes to the development of hypertension in a chronic inflammatory disease through increased renal nuclear factor κB, oxidative stress, and inflammation.

Rosiglitazone reduces blood pressure in female Dahl salt-sensitive rats.

Postmenopausal women (PMW) are at greater risk for salt-sensitive hypertension and insulin resistance than premenopausal women. Peroxisome-proliferator-activated receptor-gamma (PPARgamma) agonists reduce blood pressure (BP) and insulin resistance in humans. As in PMW, ovariectomy (OVX) increases salt sensitivity of BP and body weight in Dahl salt-sensitive (DS) rats. This study addressed whether rosiglitazone (ROSI), a PPARgamma agonist, attenuates salt-sensitive hypertension in intact (INT) and OVX DS rats, and if so, whether insulin resistance, nitric oxide (NO), oxidative stress, and/or renal inflammation were contributing mediators. Telemetric BP was similar in OVX and INT on low salt diet (0.3% NaCl), but was higher in OVX than INT on high salt (8% NaCl). ROSI reduced BP in OVX and INT on both low and high salt diet, but only attenuated salt sensitivity of BP in OVX. Nitrate/nitrite excretion (NO(x); index of NO) was similar in INT and OVX on low salt diet, and ROSI increased NO(x) in both groups. High salt diet increased NO(x) in all groups but ROSI only increased NO(x) in OVX rats. OVX females exhibited insulin resistance, increases in body weight, plasma leptin, cholesterol, numbers of renal cortical macrophages, and renal MCP-1 and osteopontin mRNA expression compared to INT. ROSI reduced cholesterol and macrophage infiltration in OVX, but not INT. In summary, PPARgamma activation reduces BP in INT and OVX females, but attenuates the salt sensitivity of BP in OVX only, likely due to increases in NO and in part to reductions in renal resident macrophages and inflammation.

Role of reactive oxygen species in hypertension produced by reduced uterine perfusion in pregnant rats.

BACKGROUND: Although recent studies indicate preeclampsia (PE) is associated with increased oxidative stress, the role of reactive oxygen species in the hypertension associated with PE remains unclear. We sought to test the hypothesis that placental ischemia increases oxidative stress which in turn, contributes to hypertension. METHODS: Reduction in uterine perfusion pressure (RUPP) was induced by placing silver clips on the abdominal aorta and the ovarian arteries on day 14 of pregnancy. On day 20 of pregnancy, mean arterial pressure (MAP) was measured and oxidative stress was assessed in renal and placental tissues whereas systemic administration of tempol, a superoxide dismutase (SOD) mimetic, was used to evaluate the contribution of reactive oxygen species on RUPP-induced hypertension. RESULTS: MAP (120 +/- 2 mm Hg vs.106 +/- 3 mm Hg), placental levels of 8-isoprostane (1.9 +/- 0.4 ng/g tissue vs. 0.8 +/- 0.1 ng/g tissue), and malondialdehyde (MDA) (6.9 +/- 0.6 micromol/g tissue vs. 3.9 +/- 0.4 micromol/g tissue) were increased, whereas renal cortical SOD activity was decreased in RUPP rats (1.2 +/- 0.1 units/mg protein vs. 1.6 +/- 0.1 units/mg protein) at day 20 of gestation (20 dG) compared to controls. Chronic treatment with tempol attenuated the hypertension (RUPP + tempol 112 +/- 2 mm Hg vs. RUPP, 120 +/- 2 mm Hg) associated with RUPP, whereas tempol had no effect on MAP (NP, 106 +/- 3 vs. NP + tempol, 108 +/- 2) in control rats. CONCLUSION: The results of this study indicate that placental ischemia decreases innate antioxidant activity resulting in elevated oxidative stress which appears to play a role in mediating hypertension associated with chronic RUPP in pregnant rats.

Pathophysiology of hypertension during preeclampsia: linking placental ischemia with endothelial dysfunction.

Studies over the last decade have provided exciting new insights into potential mechanisms underlying the pathogenesis of preeclampsia. The initiating event in preeclampsia is generally regarded to be placental ischemia/hypoxia, which in turn results in the elaboration of a variety of factors from the placenta that generates profound effects on the cardiovascular system. This host of molecules includes factors such as soluble fms-like tyrosine kinase-1, the angiotensin II type 1 receptor autoantibody, and cytokines such as tumor necrosis factor-alpha, which generate widespread dysfunction of the maternal vascular endothelium. This dysfunction manifests as enhanced formation of factors such as endothelin, reactive oxygen species, and augmented vascular sensitivity to angiotensin II. Alternatively, the preeclampsia syndrome may also be evidenced as decreased formation of vasodilators such as nitric oxide and prostacyclin. Taken together, these alterations cause hypertension by impairing renal pressure natriuresis and increasing total peripheral resistance. Moreover, the quantitative importance of the various endothelial and humoral factors that mediate vasoconstriction and elevation of arterial pressure during preeclampsia remains to be elucidated. Thus identifying the connection between placental ischemia/hypoxia and maternal cardiovascular abnormalities in hopes of revealing potential therapeutic regimens remains an important area of investigation and will be the focus of this review.