The Role of Syncytin in Placental Angiogenesis and Fetal Growth

Abstract

Background: Syncytin, a retroviral envelope protein, is specifically expressed on trophoblast cells and mediates formation of the syncytiotrophoblast through fusogenic activity. Decreased expression of Syncytin was found in fetal growth restriction placentas.Results: By generating an inducible knockout of the syncytin-a gene in mice, we show a specific disruption of placental angiogenesis with abnormal formation of two syncytiotrophoblast layers. Consistent with the defects observed in vivo, conditioned medium collected from trophoblast cells, following Syncytin-1 knockdown, contains lower expression of vascular endothelial growth factor and placental growth factor, and higher levels of soluble fms-like protein kinase-1 in BeWo and HTR-8/SVneo cells which related with suppressed PI3K/Akt/mTOR pathway, and is reduced in ability to induce tube formation by HUVECs.Conclusion: Syncytin participates in angiogenesis during placental development was first identified both in vivo and in vitro. Here, we give a new sight on understanding syncytin and pathophysiology of placenta related disease such as fetal growth restriction.

Disruption of maternal vascular remodeling by a fetal endoretrovirus-derived gene in preeclampsia

“…The genes and products of endoretroviruses are often expressed in the placenta [ 117 – 119 ], with the promoter of retroviral genes serving as species-specific enhancer elements that are specifically active in the placenta [ 120 – 123 ]. The incorporation of endoretrovirus-encoded envelop proteins, such as Syncytin I and II, promotes trophoblast fusion, resulting in the formation of multi-nuclei giant cells that line the maternal–fetal interface [ 124 – 129 ]. Interestingly, various animal taxa have exhibited the incorporation of envelop proteins from various retroviruses, suggesting convergent selection of retrovirus-gene-mediated placental features [ 117 , 124 , 130 – 138 ].…”

Development of evolutionarily conserved viral integration sites as safe harbors for human gene therapy

“…In contrast, although Dep. 35 and Proto.176-derived colonies also showed widespread expression across the four lineages, the GFP signal was dramatically reduced (Fig. 2g and Fig.…”

“…An extensive phylogenetic analysis of EPVs in vertebrate genomes disclose clear homology to members of extant parvovirus genera, including Amdoparvovirus 32 , Protoparvovirus 33,34 , and Dependoparvovirus 31,35 . The viral DNA endogenization represents an alternative to random mutation where large-step mutations resulted in the acquisition of novel viral “alleles,” facilitated genomic rearrangements, disrupted gene expression, created novel transcription factor binding sites, or resulted in “exaptation” of viral genes with potential benefits to the host organisms 36 , notably syncytin - a retrovirus envelope protein co-opted by placental mammals for trophoblast fusion early in embryogenesis 37 . Thus, identifying human orthologous sites to EPVs in non-human vertebrate genomes may indicate suitable sites for gene addition.…”

Reproductive Immunology and Pregnancy 2.0

“…Syncytin-1 is involved in fusogenic processes, during which cytotrophoblast cells continuously fuse with the overlying syncytiotrophoblast layers to establish barrier functions and transport activities [7]. In addition, the nonfusogenic effects of syncytin may be responsible for pathological placental morphogenesis based on increased apoptosis and proliferation [8]. Disturbed syncytin-1 expression is associated with increased risk of infertility, pre-eclampsia and FGR, but it has also been observed in patients with tumors such as neuroblastomas, endometrial cancer, and endometriosis [8,9].…”

“…In addition, the nonfusogenic effects of syncytin may be responsible for pathological placental morphogenesis based on increased apoptosis and proliferation [8]. Disturbed syncytin-1 expression is associated with increased risk of infertility, pre-eclampsia and FGR, but it has also been observed in patients with tumors such as neuroblastomas, endometrial cancer, and endometriosis [8,9]. Poor placental angiogenesis is a typical histopathological feature of syncytin-1 functional disruption and is often found in patients with pre-eclampsia [10].…”