{"title":"Targeting A2M-LRP1 reverses uterine spiral artery remodeling disorder and alleviates the progression of preeclampsia.","authors":"Zhengrui Huang, Ping Zhang, Ruiping Chen, Lu Sun, Jingyun Wang, Ruiling Yan, Mengyuan Liu, Yuzhen Ding, Jian Wang, Jiachun Wei, Wanchang Yin, Xinyao Lu, Guang Wang, Xuesong Yang, Ruiman Li","doi":"10.1186/s12964-025-02060-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Patients with early-onset preeclampsia (EOPE) have a most severe disease state. a2-macroglobulin (A2M) play a crucial role in the pathogenesis of EOPE, but its molecular basis and therapeutic potential remain unclear. This study aimed to elucidate the mechanisms of A2M in EOPE progression and explore the potential of A2M in the treatment of EOPE.</p><p><strong>Methods: </strong>A2M-Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) blocker Receptor-associated protein (RAP) were utilized to alleviate the disease symptom of lipopolysaccharide (LPS) induced preeclampsia rat model. RNA-seq data sourced from public databases and morphological experiments were utilized to examine the relationship between the main fate of smooth muscle cell (SMC) during uterine spiral artery remodeling (SPA-REM) and A2M. Proteomic sequencing analysis of A2M overexpression rat placenta was used to identify the underlying mechanism. Further, LC-MS/MS analysis combined with Co-immunoprecipitation (Co-IP) was used to examine the interacting between A2M and underlying mechanism.</p><p><strong>Results: </strong>Single-cell analysis and morphological experimental results suggest that SMC phenotype switching disorder is the main fate of SMC in the pathological of SPA-REM disorder, and A2M has a causal relationship with this process. Proteomic sequencing data suggest that A2M participates in this process through the RhoA-GTPase pathway, further experimental data provide evidences that A2M can directly upregulate RhoA-GTPase. Cytological and explant experiments suggest that RAP has better efficacy than A2M knockdown AAV vector, finally the efficacy of RAP was verified in the rat model of preeclampsia.</p><p><strong>Conclusion: </strong>SMC A2M promotes the progression of preeclampsia by directly upregulating RhoA-GTPase. Our findings also reveal that A2M serve as a potential target for EOPE and provide a preliminary therapy for inhibit the combination of A2M-LRP1.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"107"},"PeriodicalIF":8.2000,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852582/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Communication and Signaling","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s12964-025-02060-y","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
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Abstract
Background: Patients with early-onset preeclampsia (EOPE) have a most severe disease state. a2-macroglobulin (A2M) play a crucial role in the pathogenesis of EOPE, but its molecular basis and therapeutic potential remain unclear. This study aimed to elucidate the mechanisms of A2M in EOPE progression and explore the potential of A2M in the treatment of EOPE.
Methods: A2M-Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) blocker Receptor-associated protein (RAP) were utilized to alleviate the disease symptom of lipopolysaccharide (LPS) induced preeclampsia rat model. RNA-seq data sourced from public databases and morphological experiments were utilized to examine the relationship between the main fate of smooth muscle cell (SMC) during uterine spiral artery remodeling (SPA-REM) and A2M. Proteomic sequencing analysis of A2M overexpression rat placenta was used to identify the underlying mechanism. Further, LC-MS/MS analysis combined with Co-immunoprecipitation (Co-IP) was used to examine the interacting between A2M and underlying mechanism.
Results: Single-cell analysis and morphological experimental results suggest that SMC phenotype switching disorder is the main fate of SMC in the pathological of SPA-REM disorder, and A2M has a causal relationship with this process. Proteomic sequencing data suggest that A2M participates in this process through the RhoA-GTPase pathway, further experimental data provide evidences that A2M can directly upregulate RhoA-GTPase. Cytological and explant experiments suggest that RAP has better efficacy than A2M knockdown AAV vector, finally the efficacy of RAP was verified in the rat model of preeclampsia.
Conclusion: SMC A2M promotes the progression of preeclampsia by directly upregulating RhoA-GTPase. Our findings also reveal that A2M serve as a potential target for EOPE and provide a preliminary therapy for inhibit the combination of A2M-LRP1.
期刊介绍：
Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior.
Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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