The role of the annexin A protein family at the maternal-fetal interface.

Disruptions of the components at the maternal–fetal interface could lead to placenta dysfunction, including impairing trophoblast invasion function, hindering angiogenesis in the uterus, affecting the process of decidualization, and compromising maternal–fetal immune tolerance ( 55 , 56 ). Such disturbances are implicated in a spectrum of pregnancy-related complications. Within the human body exists a regulatory network characterized by both precision and complexity, and many mechanistic experiments are conducted utilizing some specific cell lines in vitro . Many antibodies and molecules existing in the peripheral blood play a unique role at the maternal–fetal interface. For instance, research has shown that antiphospholipid antibodies (aPLs) interacting with β2-glycoprotein I (β2GPI) modulate the expression of Bcl-2 and Bax proteins in primary human trophoblasts ( 57 ). Furthermore, the influence of anti-transglutaminase type 2 (anti-TG2) autoantibodies on endometrial angiogenesis has been explored using human endometrial endothelial cells (HEECs), shedding light on potential pathogenic mechanisms underlying placental damage in celiac disease ( 58 ). Additionally, recent findings indicate the presence of HLA-DR in STBs and STB-derived extracellular vesicles (STEVs) in a significant number of preeclampsia cases, as opposed to control placentas, suggesting a novel avenue of investigation in placental pathology in preeclampsia ( 59 ). Alterations in the expression levels of the annexin A proteins are also proven to interrupt those key processes in the establishment of pregnancy. In human-assisted reproductive technology (ART) programs, more than 60% of women treated with in-vitro fertilization (IVF) procedures fail to achieve clinical pregnancy after their first transfer and almost 20% of them suffer from unexplained recurrent implantation failures (RIFs) ( 60 ). RIF can be defined as failure to clinical pregnancy in a woman under 40 after the transfer of at least four good-quality embryos in at least three fresh or frozen cycles ( 61 ). The protein S100-A10 (S100A10), a binding partner of AnxA2, was identified as a critical factor in endometrial receptivity attainment and was downregulated in the mid-secretory phase of the endometrium of infertile women ( 62 ). Recent studies have reported that maternal and paternal M2/ANXA5 haplotype carriages are both risk factors for RIF, which shed light on the pathogenesis of RIF and provided possible forecasts for couples who are at a pertinent risk ahead of the ART programs ( 63 ). Recurrent pregnancy loss (RPL) is defined as at least two or three spontaneous miscarriages before the 24th gestational week and impacts approximately 1%–3% of reproductive-age women ( 64 ). Anatomical abnormalities, endocrine disorders, genetic factors, and immunological factors are considered responsible for RPL; however, almost half of the patients suffered for unexplained reasons ( 65 – 67 ). The role of AnxA5 in RPL has been extensively investigated since Rand JH et al. found that the level of AnxA5 and its anticoagulant activity are significantly reduced in the plasma of RPL patients ( 68 ). Moreover, the variants of ANXA5 in the placenta are found important in the pathology of RPL. The haplotype M1 is defined as the combination of two alleles, namely, c.−448 ANC and c.−422 TNC, and reveals single nucleotide polymorphisms (SNPs) of 1A/C and 27T/C. The M2 haplotype, on the other hand, is identified as having four small alleles corresponding to these four SNPs, rs112782763 (c.−467 GNA), rs28717001 (c.−448 ANC), rs28651243 (c.−422 TNC), and rs113588187 (c.−373 GNA), which contains a combination of SNPs of 19G/A, 1A/C, 27T/C, and 76G/A and can be passed on to the offspring ( 69 , 70 ). Several independent studies have shown that the M2 haplotype in ANXA5 has been linked to greater overall RPL risk mostly for early miscarriage, ranging between the 10th and 15th gestational weeks ( 71 – 73 ). A meta-analysis of 14 independent retrospective case–control studies also summarized that M2/ANXA5 haplotypes in couple populations have a significantly higher risk for RPL in comparison to the normal haplotype ( 74 ). Antiphospholipid syndrome (APS) is characterized as an autoimmune disorder that predominantly manifests in thrombotic events. It is observed that approximately 6% of patients with APS experience complications related to pregnancy ( 75 ). Extensive research indicates that antibodies in patients diagnosed with APS impede the crystallization and anticoagulant function of AnxA5. This interference leads to a diminished response to the anticoagulant properties of AnxA5 ( 43 ). Furthermore, it has been established through in-vitro studies that the application of anti-annexin V monoclonal antibodies (mAbs) precipitates apoptosis in trophoblast cells and results in a marked decrease in human chorionic gonadotropin (hCG) secretion ( 76 ). Preeclampsia (PE) refers to new-onset hypertension, proteinuria with maternal multi-organic dysfunction, or fetal growth restriction after the 20th gestational week ( 77 ). PE is the leading cause of maternal and perinatal mortality, occurring in approximately 5% of pregnancies ( 78 , 79 ). However, the pathological mechanism of PE remains obscure. It is believed that PE is related to shallow invasion of the trophoblast and poor placental perfusion at the maternal–fetal interface, as well as maternal vascular endothelial injury and vascular endothelial dysfunction accompanied by maternal systematic inflammation ( 56 , 80 ). A recent study has reported that modulation of AnxA1 in the trophoblast is associated with systemic inflammatory response-related preeclampsia ( 81 ). Using the 2D-PAGE technique, Gharesi-Fard Behrouz et al. ( 82 ) found that AnxA1, as a placental protein, is increased in PE patients, indicating exacerbated systemic inflammation in PE ( 83 ). One earlier study has reported that the AnxA2 protein both in the placenta and peripheral maternal blood was downregulated significantly in patients with PE compared with normal pregnancies, which was linked to microvascular thrombin formation in PE ( 84 ). Defects in decidualization are also considered as the maternal factor of preeclampsia ( 85 , 86 ). Researchers further found that defective expression of endometrial ANXA2 might impair the decidualization of endometrial stromal cells in vitro and in vivo , and inhibition of Anxa2 in mice failed to support embryo invasion in vivo functionally ( 32 , 87 ). Xu et al. demonstrated that ANXA4 expression is downregulated in human placentas in PE, and ANXA4 overexpression in human trophoblast cells may promote trophoblast invasion via the PI3K/AKT/eNOS pathway ( 88 ). Another systematic review, the first to combine proteomic studies of the placental biopsies of PE and polycystic ovary syndrome, found five biomarkers for PE which are common in women with PCOS, among which AnxA4 was downregulated in both groups of patients ( 89 ). In addition, the M2 haplotype of ANXA5 was also observed to be more prevalent in the placenta of women with PE compared with the controls, which may significantly increase the risk for PE by impairing the thrombomodulatory function of AnxA5 at the maternal–fetal interface ( 90 , 91 ). Small for gestational age (SGA) is defined as the birth weight of a newborn less than the 10th percentile for the corresponding gestational age ( 92 ). SGA fetuses are diagnosed with intrauterine growth retardation (IUGR) if they fail to achieve their genetically determined growth potential at any gestational age. Intrauterine growth restriction (IUGR) affects 10%–15% of all pregnancies worldwide ( 93 ). IUGR may result from maternal, placental, or fetal factors ( 94 ). Earlier studies have reported that AnxA5 is present in the amniotic fluid and increased during 15 to 24 weeks of gestation. AF-Anxa5 levels are elevated in patients who develop IUGR, which indicates AF-AnxA5 a potential marker for identifying IUGR ( 95 , 96 ). Another study further reported that decreased ANXA5 mRNA levels were detected in the placenta from SGA pregnancies in comparison to normal outcomes ( 97 ). Moreover, a recent study has demonstrated a significantly higher prevalence of the M2 haplotype in women who have delivered an SGA fetus ( 98 ), which coordinated with the extensively reported dysfunction of the ANXA5 haplotype in RPL and pre-eclampsia.

The maternal–fetal interface is a crucial site for the establishment and maintenance of normal pregnancy, where the trophoblast cells, decidual cells, and the immune microenvironment exist and interact with each other. Dysregulation of the functions of the trophoblast and disturbance of the maternal–fetal immune tolerance can lead to reproductive disorders, including infertility, spontaneous miscarriage, preeclampsia, and intrauterine growth restriction. Annexins, a well-known multigene family, are secreted proteins in the cytoplasm attaching to the phospholipid membrane and highly conservative Ca 2+ -dependent membrane-binding proteins that participate in a variety of physiological and pathological processes in humans ( 1 – 3 ). The role of the annexin family participating in several human pathologies such as tumorigenesis, obesity, and atherosclerosis has been extensively reviewed in a bunch of excellent papers ( 4 – 7 ). The expression of the annexin family was identified at the maternal–fetal interface, involving both the trophoblasts and decidual cells, but its role in successful pregnancy is not fully clear yet. Herein, we reviewed the current knowledge of the expression and possible functions of the annexin family at the maternal–fetal interface and its relationship with female reproductive diseases.

The expression of annexins in the maternal–fetal interface suggests their roles in embryo implantation and pregnancy. For the maternal side, the expression levels of AnxA1, AnxA2, AnxA4, and AnxA7 are found in decidual stromal cells and epithelial cells, and AnxA1, AnxA2, AnxA5, and AnxA6 are expressed in the trophoblast, especially in the apical and basal STB membranes ( Figure 1B ). In addition, there is an altered expression of annexins in women with reproductive disorders, such as recurrent implantation failure, endometriosis, adenomyosis, and recurrent pregnancy loss ( Table 1 ). However, whether the annexin family can be used as clinical markers remains uncertain, and further studies are required. Summary of the role of the annexin family in female reproductive disorders. NA, not applicable.

JH: Writing – original draft. LC: Writing – review & editing. JR: Writing – review & editing. XC: Writing – review & editing.