Hypoxic Microenvironment Promotes PTBP1 Lactonization and IGF2BP2 Read Defects Mediate the Development of Preeclampsia

Objective As an idiopathic hypertensive disorder of pregnancy, pre-eclampsia (PE) remains a major cause of maternal and neonatal morbidity and mortality, with no effective strategy for causal treatment. Methods This study was performed by downloading the Gene Expression Omnibus (GEO) database () based on the GSE173193 dataset, including single-cell sequencing data from placental samples of two PE patients and two normal controls. Placental cell subpopulations and their transcriptional heterogeneity were compared between PE and healthy pregnancies, and the mechanisms of PE cell dynamics in the hypoxic microenvironment were confirmed by in vitro experiments. Results In this study, we constructed a large-scale single-cell transcriptome ecological landscape of 26,416 cells from healthy pregnant and PE patients placenta and further identified a PE-specific CSNK2B-positive subpopulation of chorionic villous trophoblast (EVT) cells. Specifically, this study revealed that the EVT subpopulation PTBP1 was inactivated by lactonization in the hypoxic microenvironment, resulting in low expression of the N6-methyladenosine (m6A) reading protein IGF2BP2. On the basis of this, low expression of IGF2BP2 inhibits mitochondrial autophagy, causes the accumulation of damaged mitochondria, exacerbates lactic acid accumulation while inducing EVT apoptosis on the one hand. In particular, hypoxia may initially promote oxidative stress through the production of mitochondrial reactive oxygen species. on the other hand, it inhibits EVT adherent spot signaling, decreases EVT invasive ability, leads to impaired placental spiral vessel recast, and promotes PE disease process. In addition, there are interactions between abnormal metabolic signaling of PE-specific EVT subpopulations and microenvironmental immune cells, which activate metabolic inflammation. Conclusion The present study not only provides a new cell biological and genetic basis for elucidating the pathogenesis of PE, but also contributes to the design of an allopathic treatment strategy for PE. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was supported by the Natural Science Foundation of Shandong Province (ZR2021MH223). Nobody at any time received any payment or services from a third party for any aspect of the submitted work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Ethics Committee of The Affiliated Yantai Yuhuangding Hospital of Qingdao University and written consent was obtained from all patients or their legal guardians participating in the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets analyzed during the current study are available in the GEO database