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Silencing AADAC enhances trophoblast invasion and reveals a protective angiogenic role in severe preeclampsia

ABSTRACT: Background: Preeclampsia (PE) is a serious complication of pregnancy characterized by hypertension and organ dysfunction. The pathogenesis involves impaired trophoblast invasion and inadequate spiral artery remodeling, but the exact molecular mechanisms are not fully understood. Methods: This study aimed to investigate the role of arylacetamide deacetylase (AADAC) in the pathogenesis of PE and its effects on trophoblast function. Placental tissues were collected from 30 PE patients and 15 controls. RNA sequencing was performed for 6 severe PE samples and 6 control samples. AADAC expression in primary trophoblasts was validated via semiquantitative PCR and Western blotting. To investigate AADAC function under hypoxia, HTR8/SVneo cells were treated with CoCl2, and AADAC expression was manipulated through siRNA knockdown and overexpression. Invasion and tube formation assays were conducted to assess trophoblast function. Results: RNA sequencing revealed upregulated AADAC expression in placental tissue from PE patients. AADAC mRNA levels were significantly greater in placental cells from PE patients than in those from controls (p<0.01), whereas AADAC protein expression was lower (p<0.01). Subjecting HTR8/SVneo cells to hypoxia for 18 hours significantly increased AADAC mRNA and protein expression (p<0.001) and HIF1-alpha protein levels (p<0.05). Compared with those in control cells, the invasion (p<0.01) and tube formation (p<0.01) of hypoxia-treated HTR8/SVneo cells were greater after AADAC silencing. AADAC overexpression reduced tube formation (p<0.001) but did not significantly affect invasion. Conclusions: This study demonstrated that under hypoxic conditions, AADAC expression is significantly altered in human PE placental tissues and may play a role in trophoblast invasion and angiogenesis, which are key processes in the pathogenesis of PE. While further research is needed to elucidate the underlying mechanisms and confirm its clinical relevance, these findings suggest that AADAC could be a potential factor involved in the management of PE.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306283 | GEO | 2025/08/28

REPOSITORIES: GEO

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Project description:Invasion of cytotrophoblasts into uterine tissues is essential for placental development. To identify molecules regulating trophoblast invasion, mRNA signatures of purified villous (CTB, poor invasiveness) and extravillous (EVT, high invasiveness) trophoblasts isolated from first trimester human placentae and villous explant cultures, respectively, were compared using GeneChip analyses yielding 991 invasion/migration related transcripts. Several genes involved in physiological and pathologic cell invasion, including ADAM-12,-19,-28 as well as Spondin-2, were upregulated in EVT. Pathway prediction analyses identified several functional modules associated with either the invasive or the non-invasive trophoblast phenotype. One of the genes which were downregulated in the invasive mRNA pool, heme oxygenase-1 (HO-1), was selected for functional analyses. Real-time PCR analyses, Western blottting, and immunofluorescene of first trimester placentae and differentiating villous explant cultures demonstrated downregulation of HO-1 in invasive EVT as compared to CTB. Modulation of HO-1 expression in loss-of as well as gain-of function cell models (BeWo and HTR8/SVneo, respectively) demonstrated an inverse relationship of HO-1 expression with trophoblast migration in transwell and wound healing assays. Importantly, HO-1 expression led to an increase in protein levels and activity of the nuclear hormone receptor PPARgamma. Pharmacological inhibition of PPARgamma abrogated the inhibitory effects of HO-1 on trophoblast migration. Collectively, our results demonstrate that gene expression profiling of EVT and CTB can be used to unravel novel regulators of cell invasion. Accordingly, we identify heme oxygenase-1 as a negative regulator of trophoblast motility acting via upregulation of PPARgamma. Experiment Overall Design: To identify genes potentially regulating cell invasion trophoblast cells of early human gestation with distinct invasive properties were profiled. Experiment Overall Design: Distinct gene expression signatures of highly invasive EVT (n = 6) and poorly invasive CTB (n = 5) of different first trimester placentae using Affymetrix U133A GeneChips interrogating >20,000 genes were determined.

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Silencing AADAC enhances trophoblast invasion and reveals a protective angiogenic role in severe preeclampsia

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