Antiphospholipid antibodies prolong the activation of endothelial cells induced by necrotic trophoblastic debris: Implications for the pathogenesis of preeclampsia

Chen, Q.; Guo, Fang; Hensby-Bennett, Sarah; Stone, Peter; Chamley, Larry

doi:10.1016/j.placenta.2012.07.019

Cited by 20 publications

(13 citation statements)

References 20 publications

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“…Furthermore we showed a significant increase in ICAM-1 gene expression (marker of vascular dysfunction) in HUVEC treated with preeclampsia plasma. This correlates with previous work, which reported elevated ICAM-1 expression in preeclampsia31 and in HUVEC’s exposed to pathogenic necrotic trophoblast debris32. Furthermore, a recent transcriptomic study in HUVEC exposed to preeclampsia plasma established perturbation in pathways mediating endothelial homeostasis33.…”

Section: Discussionsupporting

confidence: 90%

Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia

McCarthy

Kenny

2016

Sci Rep

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Aberrant placentation generating placental oxidative stress is proposed to play a critical role in the pathophysiology of preeclampsia. Unfortunately, therapeutic trials of antioxidants have been uniformly disappointing. There is provisional evidence implicating mitochondrial dysfunction as a source of oxidative stress in preeclampsia. Here we provide evidence that mitochondrial reactive oxygen species mediates endothelial dysfunction and establish that directly targeting mitochondrial scavenging may provide a protective role. Human umbilical vein endothelial cells exposed to 3% plasma from women with pregnancies complicated by preeclampsia resulted in a significant decrease in mitochondrial function with a subsequent significant increase in mitochondrial superoxide generation compared to cells exposed to plasma from women with uncomplicated pregnancies. Real-time PCR analysis showed increased expression of inflammatory markers TNF-α, TLR-9 and ICAM-1 respectively in endothelial cells treated with preeclampsia plasma. MitoTempo is a mitochondrial-targeted antioxidant, pre-treatment of cells with MitoTempo protected against hydrogen peroxide-induced cell death. Furthermore MitoTempo significantly reduced mitochondrial superoxide production in cells exposed to preeclampsia plasma by normalising mitochondrial metabolism. MitoTempo significantly altered the inflammatory profile of plasma treated cells. These novel data support a functional role for mitochondrial redox signaling in modulating the pathogenesis of preeclampsia and identifies mitochondrial-targeted antioxidants as potential therapeutic candidates.

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Section: Discussionsupporting

confidence: 90%

Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia

McCarthy

Kenny

2016

Sci Rep

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“…Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis [77–79] and preeclampsia [80–83]. Activated endothelial cells with overexpression of cell-surface ICAM-1 [84–86] are more resistant to trophoblast displacement than non-activated endothelial cells [87], and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes associated with failure of physiologic transformation of the spiral arteries.…”

Section: Introductionmentioning

confidence: 99%

Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta

Labarrere

DiCarlo

Bammerlin

et al. 2017

American Journal of Obstetrics and Gynecology

129

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Background Failure of physiologic transformation of spiral arteries has been reported in preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm labor with intact or ruptured membranes. Spiral arteries with failure of physiologic transformation are prone to develop atherosclerotic-like lesions of atherosis. There are striking parallels between preeclampsia and atherosclerotic disease, and between lesions of atherosis and atherosclerosis. Endothelial activation, identified by intercellular adhesion molecule-1 expression, is present in atherosclerotic-like lesions of heart transplantation and considered a manifestation of rejection. Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis and preeclampsia. Intercellular adhesion molecule-1-overexpressing-activated endothelial cells are more resistant to trophoblast displacement than nonactivated endothelium and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes having failure of physiologic transformation. Objective To determine whether failure of spiral artery physiologic transformation was associated with activation of interstitial extravillous trophoblasts and/or spiral artery endothelium and presence of acute atherosis in the placental basal plate. Study Design A cross-sectional study of 123 placentas (19-42 weeks’ gestation) obtained from normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15), and small for gestational age (n = 10) was performed. Failure of spiral artery physiologic transformation and presence of cell activation was determined using immunohistochemistry of placental basal plates containing a median of 4 (minimum: 1; maximum: 9) vessels per placenta. Endothelial/trophoblast cell activation was defined by the expression of intercellular adhesion molecule-1 (ICAM-1). Investigators examining microscopic sections were blinded to clinical diagnosis. Pairwise comparisons among placenta groups were performed with the Fisher’s exact and Wilcoxon rank sum tests using a Bonferroni-adjusted level of significance (.025). Results 87% (94/108) of placentas having spiral arteries with failure of physiologic transformation (actin-positive and cytokeratin-negative) in the basal plate, and 0% (0/15) of placentas having only spiral arteries with complete physiologic transformation (cytokeratin-positive and actin-negative), had arterial endothelial and/or interstitial extravillous trophoblasts reactive with the ICAM-1 activation marker (P < .001). A significant correlation (R2 = 0.84) was found between expression of spiral artery endothelial and interstitial extravillous trophoblast ICAM-1 (P < .001) in activated placentas. Lesions of atherosis were found in 31.9% (30/94) of placentas with complete and/or partial failure of physiologic transformation of spiral arteries that were ICAM-1-positive, in none of the 14 placentas with failure of physiolog...

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“…Our study was underpowered to assess more than one predictive factor for pregnancy complications. Therefore, although we noticed a difference in the incidence of PE between aPL positive (4/29, 17%) and aPL negative (0/41) patients ( p = 0.03), confirming that the onset of PE is highly related to the presence of aPL antibodies as already reported in the literature, we could not dissect the individual role of mUtA PI and aPL in predicting PE. It has in fact been suggested that, in pregnancies complicated with SLE, the main risk factors for APO, despite of the administration of the standard therapy with LDA and/or low molecular weight heparin (LMWH), are the triple aPL positivity, the anamnestic venous thrombosis, and the concomitant autoimmune disease.…”

Section: Discussionmentioning

confidence: 99%

The role of second trimester uterine artery Doppler in pregnancies with systemic lupus erythematosus

et al. 2015

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Antiphospholipid antibodies prolong the activation of endothelial cells induced by necrotic trophoblastic debris: Implications for the pathogenesis of preeclampsia

Cited by 20 publications

References 20 publications

Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia

Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia

Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta

The role of second trimester uterine artery Doppler in pregnancies with systemic lupus erythematosus

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