Reduced uterine perfusion pressure model is not successful to mimic severe preeclampsia

Balta, Oya; Boztosun, Abdullah; Deveci, Köksal; Gültürk, Sefa; Ekici, Filiz; Kaya, Ali; Çetin, Ali; Çetin, Meral

doi:10.1016/j.placenta.2011.06.005

Cited by 16 publications

(10 citation statements)

References 31 publications

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“…However, sCR1 effectively inhibited this complement activation as evidenced by decreased C3a concentrations in RUPP sCR1 animals. As previously reported (Balta et al, 2011) and confirmed in our studies, RUPP surgery with clip placement in a non-pregnant female rat did not increase blood pressure. In addition, C3a did not significantly change over a 5 day period in a non-pregnant female with RUPP surgery and clip placement (C3a change of 0.05±0.07 units/μl).…”

Section: Resultssupporting

confidence: 93%

“…In addition, placental ischemia as the initiator of hypertension allows concurrent inflammatory and angiogenic pathways to operate in situ resulting in hypertension. The RUPP procedure is an established and effective means of inducing hypertension following placental ischemia in animal models and closely mimics many characteristics of preeclampsia (Li et al, 2012) without inducing symptoms of severe preeclampsia (Balta et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

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Complement activation is critical for placental ischemia-induced hypertension in the rat

Lillegard

Johnson

Lojovich

et al. 2013

Molecular Immunology

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Preeclampsia is a major obstetric problem defined by new-onset hypertension and proteinuria associated with compromised placental perfusion. Although activation of the complement system is increased in preeclampsia compared to normal pregnancy, it remains unclear whether excess complement activation is a cause or consequence of placental ischemia. Therefore, we hypothesized that complement activation is critical for placental ischemia-induced hypertension. We employed the reduced utero-placental perfusion pressure (RUPP) model of placental ischemia in the rat to induce hypertension in the third trimester and evaluated the effect of inhibiting complement activation with a soluble recombinant form of an endogenous complement regulator, human complement receptor 1 (sCR1; CDX-1135). On day 14 of a 21-day gestation, rats received either RUPP or Sham surgery and 15 mg/kg/day sCR1 or saline intravenously on days 14–18. Circulating complement component 3 decreased and complement activation product C3a increased in RUPP vs Sham (p<0.05), indicating complement activation had occurred. Mean arterial pressure (MAP) measured on day 19 increased in RUPP vs Sham rats (109.8±2.8 mmHg vs 93.6±1.6 mmHg). Treatment with sCR1 significantly reduced elevated MAP in RUPP rats (98.4±3.6 mmHg, p<0.05) and reduced C3a production. Vascular endothelial growth factor (VEGF) decreased in RUPP compared to Sham rats, and the decrease in VEGF was not affected by sCR1 treatment. Thus, these studies have identified a mechanistic link between complement activation and the pregnancy complication of hypertension apart from free plasma VEGF and have identified complement inhibition as a potential treatment strategy for placental ischemia-induced hypertension in preeclampsia.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Complement activation is critical for placental ischemia-induced hypertension in the rat

Lillegard

Johnson

Lojovich

et al. 2013

Molecular Immunology

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“…Although similar approaches have been taken in several other species, including primates (Makris et al, 2007), this has been most commonly used in the rat, resulting in nearly 80 publications. The RUPP model exhibits proteinuria, hypertension, increased levels of sFLT-1 and the inflammatory cytokine interleukin-6 (IL-6), reduced levels of PLGF, and fetal growth restriction (Gadonski et al, 2006; Granger et al, 2006; Balta et al, 2011; George et al, 2011), making it an excellent potential model to test treatments that address any of these symptoms of preeclampsia. However, placentas in the RUPP model do not exhibit reduced trophoblast invasion, a key aspect of preeclampsia.…”

Section: Models Of Preeclampsiamentioning

confidence: 99%

“…Aspirin irreversibly inhibits the production of thromboxine A2 in platelets and thereby inhibits platelet aggregation, so the use of this relatively common and presumably safe medication seemed to offer a biologically plausible intervention. Additional in vitro and animal studies suggested that early abnormalities in trophoblast-mediated maternal spiral artery remodeling (Abitbol, 1982; Balta et al, 2011; Hung et al, 2001; Makris et al, 2007; Li et al, 2010) might result in hypoxia-reoxygenation injury in the placenta secondary to oxidative damage. These studies provide further rationale for use of low-dose aspirin for the prevention of preeclampsia, owing to a different mechanism of action: the known ability of aspirin to modulate thromboxane- but not prostacyclin-mediated vasoconstriction (Masotti et al, 1979; Thorp et al, 1988).…”

Section: Translation Of Preeclampsia Models Into Clinical Testing Andmentioning

confidence: 99%

Preeclampsia: multiple approaches for a multifactorial disease

Pennington

Schlitt

Jackson

et al. 2012

Disease Models &Amp; Mechanisms

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211

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Preeclampsia is a pregnancy-specific disorder characterized by hypertension and excess protein excretion in the urine. It is an important cause of maternal and fetal morbidity and mortality worldwide. The disease is almost exclusive to humans and delivery of the pregnancy continues to be the only effective treatment. The disorder is probably multifactorial, although most cases of preeclampsia are characterized by abnormal maternal uterine vascular remodeling by fetally derived placental trophoblast cells. Numerous in vitro and animal models have been used to study aspects of preeclampsia, the most common being models of placental oxygen dysregulation, abnormal trophoblast invasion, inappropriate maternal vascular damage and anomalous maternal-fetal immune interactions. Investigations into the pathophysiology and treatment of preeclampsia continue to move the field forward, albeit at a frustratingly slow pace. There remains a pressing need for novel approaches, new disease models and innovative investigators to effectively tackle this complex and devastating disorder.

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“…Although the pathophysiological mechanisms underlying these pregnancy complications remain elusive, superficial and incomplete trophoblast invasion and maternal vascular-deficient remodelling leading to placental ischaemia and hypoxia seem to be recurrent in pre-eclampsia and IUGR (Balta et al, 2011;Roberts and Post, 2008;Watson and Cross, 2005). Moreover, some evidence exists that abnormal release of factors by the placenta syncytium can cause damage to the maternal endothelium (de Jager et al, 2003;Guller, 2009).…”

Section: Introductionmentioning

confidence: 99%

Implication of MEK1 and MEK2 in the establishment of the blood–placenta barrier during placentogenesis in mouse

Charron

Bissonauth

Nadeau

2012

Reproductive BioMedicine Online

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The ERK/MAPK signalling cascade is involved in many cellular functions. In mice, the targeted ablation of genes coding for members of this pathway is often associated with embryonic death due to the abnormal development of the placenta. The placenta is essential for nutritional and gaseous exchanges between maternal and embryonic circulations, as well as for the elimination of metabolic waste. These exchanges occur without direct contact between the two circulations. In mice, the blood-placenta barrier consists of a triple layer of trophoblast cells adjacent to endothelial cells from the embryo. In the ERK/MAPK cascade, MEK1 and MEK2 are dual-specificity kinases responsible for the activation of the ERK1 and ERK2 kinases. Inactivation of Mek1 causes placental malformations resulting from defective proliferation and differentiation of the labyrinthine trophoblast cells and leading to a severe delay in the development and the vascularization of the placenta, which explains the embryonic death. Although Mek2(-/-) mutants survive without any apparent phenotype, a large proportion of Mek1(+/-)Mek2(+/-) double heterozygous mutants die during gestation from placenta anomalies affecting the establishment of the blood-placenta barrier. Together, these data reveal how crucial is the role of the ERK/MAPK pathway during the formation of the placenta.

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Reduced uterine perfusion pressure model is not successful to mimic severe preeclampsia

Cited by 16 publications

References 31 publications

Complement activation is critical for placental ischemia-induced hypertension in the rat

Complement activation is critical for placental ischemia-induced hypertension in the rat

Preeclampsia: multiple approaches for a multifactorial disease

Implication of MEK1 and MEK2 in the establishment of the blood–placenta barrier during placentogenesis in mouse

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