Reduced ANXA5 mRNA and protein expression in pregnancies complicated by preeclampsia

Gourvas, Victor; Soulitzis, Nikolaos; Konstantinidou, Anastasia; Dalpa, Efterpi; Koukoura, Ourania; Koutroulakis, Demetrios; Spandidos, Demetrios Α.; Sifakis, Stavros

doi:10.1016/j.thromres.2013.12.027

Cited by 13 publications

(7 citation statements)

References 34 publications

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“…Since 2007, much work has been accumulated on a newly identified hereditary thrombophilic genetic factor, the 'M2 haplotype' of the annexin A5 (ANXA5) gene. Indeed, we and others identified the M2 haplotype associated with obstetric pathologies such as gestational hypertension, preeclampsia [23][24][25][26][27], fetal growth restriction, preterm birth [26,[28][29][30], antiphospholipid syndrome [31], and most incriminatory recurrent pregnancy losses (RPL) [32]. Moreover, in our previous studies, we confirmed risks of maternal M2/ANXA5 haplotype and identified the paternal carrier status as an equal risk factor for RPL and obstetric complications [23,33].…”

Section: Introductionsupporting

confidence: 76%

Maternal and paternal carriage of the annexin A5 M2 haplotype: a possible risk factor for recurrent implantation failure (RIF)

Rogenhofer

Markoff²,

Ennerst

et al. 2020

J Assist Reprod Genet

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Objective This study was carried out to determine the potential role of the M2/ANXA5 haplotype as a risk factor for recurrent implantation failure (RIF). Carriage of the M2/ANXA5 haplotype that induces prothrombotic changes has been implicated in failure of early pregnancies and placenta-mediated complications (preeclampsia, IUGR, preterm birth). Material and methods In the present case control study, 63 couples (females and males) with RIF presenting for IVF/ICSI to the Fertility Center of [masked] were analyzed. RIF was defined as ≥ 4 consecutive failed ART-transfers of ≥ 4 blastocysts or ≥ 8 cleavage-stage embryos of optimal quality and maternal age ≤ 41. Fertile female controls (n = 90) were recruited from the same center. Population controls (n = 533) were drafted from the PopGen biobank, UKSH Kiel. Results Couples carrying the M2/ANXA5 haplotype turned out to have a significantly increased relative risk (RR) for RIF. Compared with female fertile controls, RR was 1.81 with p = 0.037 (OR 2.1, 95%CI 1.0–4.3) and RR was 1.70, with p = 0.004 (OR 2.0, 95%CI 1.2–3.1) compared with population controls (15.4% M2 carriers). Male partners were comparable with RIF females for M2/ANXA5 haplotypes (28.6% vs. 23.8%, p = 0.54). RIF females compared with population controls had a RR of 1.55 (p = 0.09) and RIF males compared with population controls had a RR of 1.9 (p = 0.01). Couples with ≥ 7 failed transfers showed a RR of 1.82 (p = 0.02) compared with population controls. Conclusion Our findings suggest that maternal as well as paternal M2/ANXA5 haplotype carriages are risk factors for RIF. These results allow new insights into the pathogenesis of RIF and might help to identify relevant risk groups.

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Section: Introductionsupporting

confidence: 76%

Maternal and paternal carriage of the annexin A5 M2 haplotype: a possible risk factor for recurrent implantation failure (RIF)

Rogenhofer

Markoff²,

Ennerst

et al. 2020

J Assist Reprod Genet

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“…Up to 2.7-fold decreased transcription efficiency has been shown for the M2 haplotype in the HeLa cells in vitro , however the observed effect remains to be confirmed in the placental cells [ 10 ]. Furthermore, the strongly reduced levels of ANXA5 mRNA are only mildly reflected at protein level indicating a redundancy in annexin A5 metabolism [ 18 , 30 , 39 – 40 ]. For example in placental samples of pre-eclampsia, the ANXA5 mRNA expression level was reduced to 1%, while the protein level remained at 65% of the average normal expression [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previously, ANXA5 has been reported as a protein that forms a protective antithrombotic shield at the surface of placental syncytiotrophoblasts [ 15 ]. Disruption of this layer and reduced levels of annexin A5 protein on the placental villi have been considered a risk factor leading to increased incidence of pre-eclampsia and early pregnancy loss as demonstrated for women with antiphospholipid and anti-annexin A5 antibodies [ 16 – 18 ]. Most recently, ANXA5 has been described as an endogenous membrane repair protein essential for the integrity of a healthy placenta [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Annexin A5 Promoter Haplotype M2 Is Not a Risk Factor for Recurrent Pregnancy Loss in Northern Europe

et al. 2015

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IntroductionAnnexin A5 is an essential component of placental integrity that may potentially mediate susceptibility to phenotypes of compromised pregnancy. A promoter haplotype termed M2 of the coding gene ANXA5 has been implicated in various pregnancy complications such as preeclampsia and recurrent pregnancy loss (RPL), however with inconclusive results.Study subjects and methodsA retrospective case-control study combining resequencing and restriction fragment length polymorphism (RFLP) analysis was undertaken in 313 women with unexplained RPL and 214 fertile women from Estonia and Denmark to estimate the RPL disease risk of the M2 haplotype in Northern Europe. Comparative prevalence of the studied ANXA5 genetic variants in human populations was estimated based on the 1000 Genomes Project (n = 675, whole-genome sequencing data) and the KORA S3 500K dataset of South German samples (n = 1644, genome-wide genotyping data).ResultsMinor allele frequency of common polymorphisms in ANXA5 promoter was up to two-fold lower among Estonian RPL subjects than fertile controls. The M2 haplotype was not associated with RPL and a trend for decreased prevalence was observed among RPL patients compared to controls both in Estonia (8.1% vs 15.2%, respectively) and Denmark (9.7% vs 12.6%). The high M2 prevalence in fertile controls was consistent with estimations for European and East Asian populations (9.6%-16.0%).ConclusionsThis study cautions to consider the M2 haplotype as a deterministic factor in early pregnancy success because: i) no RPL disease risk was associated with the haplotype in two clinically well-characterized RPL case-control study samples, ii) high prevalence of the haplotype among fertile controls and world-wide populations is inconsistent with the previously proposed severe impact on early pregnancy success, iii) weak impact of M2 haplotype on the production of ANXA5 protein has been established by others.

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“…IUGR and preeclampsia) 14 . Noteworthy, AnxA5 is markedly reduced in the placenta of IUGR and preeclampsia 37 38 39 . In conclusion, using a physiological model with primary culture of human trophoblasts, we report that AnxA5 forms a 2D-network at the inner-leaflet of the plasma membrane of human trophoblasts.…”

Section: Discussionmentioning

confidence: 99%

Annexin-A5 organized in 2D-network at the plasmalemma eases human trophoblast fusion

Degrelle

Gerbaud

Leconte

et al. 2017

Sci Rep

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Only a limited number of human cells can fuse to form a multinucleated syncytium. Cell fusion occurs as part of the differentiation of some cell types, including myotubes in muscle and osteoclasts in remodeling bone. In the differentiation of the human placenta, mononuclear cytotrophoblasts aggregate and fuse to form endocrinologically active, non-proliferative, multinucleated syncytia. These syncytia allow the exchange of nutrients and gases between the maternal and fetal circulation. Alteration of syncytial formation during pregnancy affects fetal growth and the outcome of the pregnancy. Here, we demonstrate the role of annexin A5 (AnxA5) in syncytial formation by cellular delivery of recombinant AnxA5 and RNA interference. By a variety of co-immunoprecipitation, immunolocalization and proximity experiments, we show that a pool of AnxA5 organizes at the inner-leaflet of the plasma membrane in the vicinity of a molecular complex that includes E-Cadherin, α-Catenin and β-Catenin, three proteins previously shown to form adherens junctions implicated in cell fusion. A combination of knockdown and reconstitution experiments with AnxA5, with or without the ability to self-assemble in 2D-arrays, demonstrate that this AnxA5 2D-network mediates E-Cadherin mobility in the plasmalemma that triggers human trophoblasts aggregation and thereby cell fusion.

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Reduced ANXA5 mRNA and protein expression in pregnancies complicated by preeclampsia

Cited by 13 publications

References 34 publications

Maternal and paternal carriage of the annexin A5 M2 haplotype: a possible risk factor for recurrent implantation failure (RIF)

Maternal and paternal carriage of the annexin A5 M2 haplotype: a possible risk factor for recurrent implantation failure (RIF)

Annexin A5 Promoter Haplotype M2 Is Not a Risk Factor for Recurrent Pregnancy Loss in Northern Europe

Annexin-A5 organized in 2D-network at the plasmalemma eases human trophoblast fusion

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