Hypertension in Response to Chronic Reductions in Uterine Perfusion in Pregnant Rats

LaMarca, Babbette; Speed, J.F.; Fournier, Lillian; Babcock, Sara A.; Berry, Hunter; Cockrell, Kathy; Granger, Joey P.

doi:10.1161/hypertensionaha.108.120881

Cited by 148 publications

(176 citation statements)

References 30 publications

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“…Exaggerated inflammatory responses were believed to be a significant pathophysiological event during preeclampsia (25). Several biochemical parameters indicate that endothelial dysfunction is related to the inflammatory response in preeclampsia, such as elevated serum cellular fibronectin, endothelial adhesion molecules P-selectin, the intercellular adhesion molecule, the vascular cell adhesion molecule, and the platelet endothelial cell adhesion molecule levels (2,19,21,31,33). A previous study reported that the pro-inflammatory cytokines increased significantly in preeclamptic women compared to women with normal pregnancies at sea level (28).…”

Section: Discussionmentioning

confidence: 99%

The effect of high altitude on endothelial and vascular dysfunction markers in preeclamptic patients

So¹,

Suekit²,

Ao³

et al. 2015

Acta Physiologica Hungarica

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Placental hypoxia, a major component of the pathophysiology of preeclampsia, is associated with various maternal vascular and endothelial dysfunctions. The higher incidence of preeclampsia at high altitude remains incompletely explained. The aim of the present study was to investigate the effect of high altitude on some endothelial and vascular dysfunction markers in normal and preeclamptic pregnancies. Eighty pregnant women (Paras 2-4) were enrolled in this study, which included four groups (each n = 20): normal pregnancies at low altitude (NL), normal pregnancies at high altitude (NH), preeclamptic pregnancies at low altitude (PL), and preeclamptic pregnancies at high altitude (PH). In normal pregnancies at high altitude serum ET-1, plasma TXA 2 , and serum TNF-α levels increased significantly with a significant reduction in plasma PGI 2 (66.81 ± 7.36, 122.86 ± 13.37, 102.23 ± 13.31, 191.57 ± 19.68, respectively) compared with the NL group (48.92 ± 4.58, 89.03 ± 10.67, 69.86 ± 7.97, 238.01 ± 24.55, respectively). In preeclampsia at low altitude serum ET-1, plasma TXA 2 , and serum TNF-α levels increased significantly with a significant reduction in plasma PGI 2 (88.39 ± 9.54, 162.73 ± 15.92, 142.39 ± 15.37, 149.155 ± 15.66, respectively) compared with both NL and NH groups. High altitude significantly augmented these changes in preeclamptic patients (117.75 ± 12.96, 211.01 ± 22.69, 196.86 ± 17.64, 111.92 ± 10.74) compared with PL, NH and NL groups. In conclusion hypoxia at high altitude aggravated the disturbances in the levels of ET-1, TXA 2 , PGI 2 and TNF-α associated with preeclampsia. This may contribute to the higher risk of preeclampsia at high altitude.

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Section: Discussionmentioning

confidence: 99%

The effect of high altitude on endothelial and vascular dysfunction markers in preeclamptic patients

So¹,

Suekit²,

Ao³

et al. 2015

Acta Physiologica Hungarica

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“…16 The increase in blood pressure observed in C1q Ϫ/Ϫ ϫC1q Ϫ/Ϫ mice, although significant when compared with control matings, is moderate. Other important factors that can increase blood pressure in pregnant mice and, thus, have been related to PE, like endothelin 1 34 or angiotensin receptor agonistic autoantibodies, 35 should be studied in this model.…”

Section: Discussionmentioning

confidence: 99%

Role of Complement Component C1q in the Onset of Preeclampsia in Mice

2011

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Abstract-Preeclampsia (PE) is a life-threatening, pregnancy-induced disease and a leading cause of maternal and fetal morbidity and mortality. Despite considerable research, the causes of PE remain unclear, and there is no effective treatment. Studies in animal models that resemble this complex pregnancy-related disorder may help to identify possible therapies for PE. Complement component C1q has an important role in trophoblast migration, spiral arteries remodeling, and normal placentation. Here we show that pregnant C1q-deficient (C1q Ϫ/Ϫ ) mice recapitulate the key features of human PE: hypertension, albuminuria, endotheliosis, decreased placental vascular endothelial growth factor (VEGF) and elevated levels of soluble VEGF receptor 1 (sFlt-1) that correlate with increased fetal death. In addition, decreased blood flow and increased oxidative stress are observed in placentas from C1q Ϫ/Ϫ mice. Treatment of C1q Ϫ/Ϫ mice with pravastatin restored trophoblast invasiveness, placental blood flow, and angiogenic balance and, thus, prevented the onset of PE. Serum-soluble receptors for VEGF-1 levels were reduced and placental VEGF levels were significantly increased in C1q Ϫ/Ϫ mice treated with pravastatin compared with untreated C1q Ϫ/Ϫ mice (VEGF: 1067Ϯ171 versus 419Ϯ194 pg/mL; PϽ0.01). Pravastatin treatment reduced hypertension (change in mean arterial pressure: 1Ϯ1 versus 18Ϯ3 mm Hg in C1q Ϫ/Ϫ untreated mice), and albuminuria (of creatinine) was reduced from 820Ϯ175 to 117Ϯ45 g/mg (both PϽ0.01). Renal damage and endothelial dysfunction were significantly attenuated with pravastatin. This model that highlights the causative role of impaired trophoblast invasion in the pathogenesis of PE allowed us to identify pravastatin as a good therapeutic option to prevent PE. Key Words: mouse model Ⅲ preeclampsia Ⅲ trophoblast invasion Ⅲ complement Ⅲ pravastatin P reeclampsia (PE), a pregnancy-specific, multisystemic disorder, is a leading cause of maternal and perinatal mortality and morbidity. 1 Because PE only occurs during pregnancy and its symptoms resolve after delivery, the placenta is thought to be crucial to the development of the disease. Indeed, several studies suggested that a defective trophoblast invasion and abnormal placentation are some of the underlying mechanisms of PE. 2,3 Conversion of the maternal spiral arteries into larger competent vessels is one of the essential steps in the development of the normal placenta. This process is apparently dependent on the invasion by trophoblasts of the subendometrial area and the spiral arteries. PE is characterized by shallow trophoblast invasion and unconverted narrow spiral arteries that leads to placental dysfunction and endothelial injury that eventually manifest as maternal hypertension and proteinuria. 4 The study of PE in women is of critical importance; however, studies in humans have obvious limitations that prevent investigation of many pathophysiological mechanisms and that often limit the ability to establish cause-andeffect relationships in pregnant...

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“…It is noteworthy that the increase in TNF production following hypertonic NaCl intake was restricted to the kidney as increases in plasma levels of TNF are generally observed in conditions where the proinflammatory actions of this cytokine contribute to the progression of pathological dysfunction. For instance, increases in plasma TNF levels are observed in pregnancy-induced hypertension and following administration of a high-salt diet to salt-sensitive Dahl-SS rats (21,34). In contrast, TNF does not increase blood pressure in normal rats and administration of 1% NaCl in the drinking water for 7 days was not associated with an increase in blood pressure (24,26).…”

Section: Discussionmentioning

confidence: 99%

NKCC2A and NFAT5 regulate renal TNF production induced by hypertonic NaCl intake

Hao

Bellner

Ferreri

2013

American Journal of Physiology-Renal Physiology

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Pathways that contribute to TNF production by the kidney are not well defined. Mice given 1% NaCl in the drinking water for 3 days exhibited a 2.5-fold increase in urinary, but not plasma, TNF levels compared with mice given tap water. Since furosemide attenuated the increase in TNF levels, we hypothesized that hypertonic NaCl intake increases renal TNF production by a pathway involving the Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC2). A 2.5-fold increase in NKCC2A mRNA accumulation was observed in medullary thick ascending limb (mTAL) tubules from mice given 1% NaCl; a concomitant 2-fold increase in nuclear factor of activated T cells 5 (NFAT5) mRNA and protein expression was observed in the outer medulla. Urinary TNF levels were reduced in mice given 1% NaCl after an intrarenal injection of a lentivirus construct designed to specifically knockdown NKCC2A (EGFP-N2A-ex4); plasma levels of TNF did not change after injection of EGFP-N2A-ex4. Intrarenal injection of EGFP-N2A-ex4 also inhibited the increase of NFAT5 mRNA abundance in the outer medulla of mice given 1% NaCl. TNF production by primary cultures of mTAL cells increased approximately sixfold in response to an increase in osmolality to 400 mosmol/kgH2O produced with NaCl and was inhibited in cells transiently transfected with a dnNFAT5 construct. Transduction of cells with EGFP-N2A-ex4 also prevented increases in TNF mRNA and protein production in response to high NaCl concentration and reduced transcriptional activity of a NFAT5 promoter construct. Since NKCC2A expression is restricted to the TAL, NKCC2A-dependent activation of NFAT5 is part of a pathway by which the TAL produces TNF in response to hypertonic NaCl intake. TNF; NFAT5; Ton/EBP; NKCC2; thick ascending limb; hypertonic stress TUMOR NECROSIS FACTOR-␣ (TNF) is produced by several cell types along the nephron including the medullary thick ascending limb of Henle's loop (mTAL), which reabsorbs ϳ25% of filtered NaCl and is the site of action for loop diuretics (12, 41). TNF acts in an autocrine manner to inhibit in vitro correlates of Na ϩ reabsorption by a mechanism involving induction of cyclooxygenase-2 (COX-2), and the contribution of this cytokine to renal function is still being defined (17). For instance, recent studies have shown that TNF exhibits natriuretic effects, exerts a tonic inhibitory effect on the Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC2), and inhibits endothelial nitric oxide synthase expression in the TAL (2,50,53,54). The mTAL produces TNF in response to several stimuli; however, knowledge regarding the pathways that contribute to TNF production by the kidney is limited (1,12,18,22,41,59).Renal medullary tonicity modulates regulatory systems that control tubular and microcirculatory function in the kidney; the molecules involved in these processes are still being explored (51). The rate of NaCl transport in the TAL is an important determinant of medullary hypertonicity, and the majority of this transport occurs via NKCC2 a 12-transmembrane-helix transport protein expressed exclusively...

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Hypertension in Response to Chronic Reductions in Uterine Perfusion in Pregnant Rats

Cited by 148 publications

References 30 publications

The effect of high altitude on endothelial and vascular dysfunction markers in preeclamptic patients

The effect of high altitude on endothelial and vascular dysfunction markers in preeclamptic patients

Role of Complement Component C1q in the Onset of Preeclampsia in Mice

NKCC2A and NFAT5 regulate renal TNF production induced by hypertonic NaCl intake

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