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Yu D, Luo L, Wang H, Shyh-Chang N. Pregnancy-induced metabolic reprogramming and regenerative responses to pro-aging stresses. Trends Endocrinol Metab 2025; 36:482-494. [PMID: 39122601 DOI: 10.1016/j.tem.2024.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/12/2024] [Accepted: 07/17/2024] [Indexed: 08/12/2024]
Abstract
Pregnancy is associated with physiological adaptations that affect virtually all organs, enabling the mother to support the growing fetus and placenta while withstanding the demands of pregnancy. As a result, mammalian pregnancy is a unique state that exerts paradoxical effects on maternal health. On one hand, the metabolic stress induced by pregnancy can accelerate aging and functional decline in organs. On the other hand, pregnancy activates metabolic programming and tissue regenerative responses that can reverse age-related impairments. In this sense, the oocyte-to-blastocyst transition is not the only physiological reprogramming event in the mammalian body, as pregnancy-induced regeneration could constitute a second physiological reprogramming event. Here, we review findings on how pregnancy dualistically leads to aging and rejuvenation in the maternal body.
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Affiliation(s)
- Dainan Yu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Lanfang Luo
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; School of Biological Engineering, Zhuhai Campus of Zunyi Medical University, Guangdong 519000, China
| | - Hongmei Wang
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Ng Shyh-Chang
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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Yang C, Song Z. CITED2 is highly-expressed and PRX4 is poorly-expressed in preeclampsia and have diagnostic values. J Hum Hypertens 2025; 39:293-300. [PMID: 40016392 DOI: 10.1038/s41371-025-00995-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 02/04/2025] [Accepted: 02/14/2025] [Indexed: 03/01/2025]
Abstract
This study aims to investigate the differential level of CITED2 and PRX4 in the serum of preeclampsia (PE) patients and to explore their clinical value in PE diagnosis, severity assessment, and pregnancy outcomes. A total of 110 singleton pregnant women with PE were included, consisting of 57 cases of mild PE and 53 cases of severe PE, with 110 healthy singleton pregnant women enrolled as the normal control. The baseline clinical characteristics were analyzed using chi-square test and independent samples t-test. CITED2 and PRX4 concentrations were measured by ELISA and their diagnostic efficacy for PE was evaluated through ROC curves. Multivariate logistic regression analysis was conducted to identify factors associated with adverse pregnancy outcomes in PE patients. Compared to the healthy group, CITED2 serum levels in PE patients were significantly increased, while PRX4 levels were significantly decreased. CITED2 and PRX4 can diagnose PE, distinguish between mild and severe PE, and be associate with adverse pregnancy outcomes in PE patients. The diagnostic efficacy was better when CITED2 and PRX4 were combined. The serum levels of CITED2 were further elevated and PRX4 levels were further reduced in patients with severe PE and adverse pregnancy outcomes. CITED2 was an independent risk factor and PRX4 was a protective factor for adverse pregnancy outcomes in PE patients. In conclusion, CITED2 and PRX4 can diagnose PE, assess PE severity, and are associated with PE outcomes.
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Affiliation(s)
- Caixia Yang
- Department of Obstetrics, Children's Hospital of Shanxi Province (Maternal and Child Health Hospital of Shanxi Province, Maternity Hospital of Shanxi Province), Taiyuan, 030013, China
| | - Zhiying Song
- Department of Obstetrics, Children's Hospital of Shanxi Province (Maternal and Child Health Hospital of Shanxi Province, Maternity Hospital of Shanxi Province), Taiyuan, 030013, China.
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Shan Y, Hu H, Chu Y. Cross-ancestry genome-wide association study identifies new susceptibility genes for preeclampsia. BMC Pregnancy Childbirth 2025; 25:379. [PMID: 40170147 PMCID: PMC11959822 DOI: 10.1186/s12884-025-07534-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 03/26/2025] [Indexed: 04/03/2025] Open
Abstract
BACKGROUND Preeclampsia (PE) is a heterogeneous, multi-organ pregnancy disorder that poses a significant health burden globally, with its pathogenesis remaining unclear. This study aimed to identify novel susceptibility genes for PE through a cross-ancestry genome-wide association study (GWAS). METHODS We performed meta-analysis to summarize the PE GWAS data from the United Kingdom, Finland, and Japan. Subsequently, the multi-ancestry sum of the single-effects model was used to perform cross-ancestry fine-mapping. The functional mapping and annotation (FUMA)-expression quantitative trait loci (eQTL) mapping method, transcriptome-wide association study (TWAS)- functional summary-based imputation (FUSION) method, genome-wide complex trait analysis (GCTA)-multivariate set-based association test (mBAT)-combo method, and polygenic priority score (PoPS) method were employed to screen for candidate genes. We utilized biomarker expression level imputation using summary-level statistics (BLISS), based on summary-level protein quantitative trait loci (pQTL) data, to conduct a multi-ancestry proteome-wide association study (PWAS) analysis, followed by candidate drug prediction. RESULTS Six novel susceptibility genes associated with PE risk were identified: NPPA, SWAP70, NPR3, FGF5, REPIN1, and ACAA1. High expression of the NPPA and SWAP70 and low expression of the remaining genes were associated with a reduced risk of PE. Furthermore, we identified drugs that target NPPA, NPR3, and REPIN1. CONCLUSIONS Our study identified NPPA, SWAP70, NPR3, FGF5, REPIN1, and ACAA1 as novel genes whose predicted expression was linked to the risk of PE, offering new insights into the genetic framework of this condition.
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Affiliation(s)
- Yuping Shan
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hong Hu
- Clinical Medicine, Nantong University, Nantong, China
| | - Yijing Chu
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China.
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Zhuang Y, Xiao Y, Bai R, Song Y, Lin Z, Yu Y, Chen Q, Wang Z. The Association of Peripheral Blood Immunoinflammatory Markers with PE and Adverse Outcomes in Preeclampsia: A Retrospective Study. J Inflamm Res 2025; 18:4359-4366. [PMID: 40162079 PMCID: PMC11954471 DOI: 10.2147/jir.s504552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 03/14/2025] [Indexed: 04/02/2025] Open
Abstract
Background Preeclampsia (PE) is a syndrome exclusive to pregnancy, presenting substantial risks to maternal and fetal health. Systemic immune-inflammatory response is a prominent feature of PE. Methods A retrospective study was conducted involving 749 pregnant women in Guangzhou, China from September 2018 to September 2024. Three hundred and seventy participants were diagnosed with PE, 166 of which had adverse pregnancy outcomes (APOs). Immuno-inflammatory markers expressed in peripheral blood were evaluated during the second-trimester. APOs included postpartum haemorrhage (PPH), premature rupture of membranes (PROM), placental abruption, fetal growth restriction, neonatal intensive care unit (NICU) transfer, and fetal distress. The relationship between immune-inflammatory markers and PE and APOs was analyzed. Results Women with PE were at higher risk of APOs and had higher levels of neutrophil-to-lymphocyte ratio (NLR), systemic immunoinflammatory index (SII) and systemic inflammatory response index (SIRI). The AUC values for NLR, SII, and SIRI with PE were 0.594, 0.649, and 0.646 (P < 0.001), with cut-off values of 4.389, 994.863, and 2.406, respectively. For APOs in PE, the AUC values were 0.632, 0.627 and 0.669, with cut-off values of 4.959, 1070.408 and 3.346, respectively. Analysis indicated higher SII levels with increased incidences of fetal growth restriction, NICU transfer and fetal distress, and SIRI levels with NICU transfer and fetal distress (P < 0.05). Conclusion Elevated levels of immune-inflammatory markers including NLR, SII, and SIRI are associated with PE and APOs. Our findings underscored the different optimal cut-off values of immune-inflammatory markers in the pregnant women between PE and the APOs.
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Affiliation(s)
- Yunting Zhuang
- Department of Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
- School of Nursing, Southern Medical University, Guangzhou, People’s Republic of China
| | - Yanxuan Xiao
- School of Nursing, Southern Medical University, Guangzhou, People’s Republic of China
| | - Ruiyan Bai
- School of Nursing, Southern Medical University, Guangzhou, People’s Republic of China
| | - Yao Song
- Department of Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
- School of Nursing, Southern Medical University, Guangzhou, People’s Republic of China
| | - Zeshan Lin
- Department of Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Yiqi Yu
- Department of Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Qian Chen
- Department of Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Zhijian Wang
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China
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Sun N, Yang K, Wang H, Zhou W. Investigating genetic links between biological aging and adverse pregnancy outcomes. Biogerontology 2025; 26:56. [PMID: 39920341 DOI: 10.1007/s10522-025-10198-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 01/28/2025] [Indexed: 02/09/2025]
Abstract
Observational studies suggest a link between biological aging and adverse pregnancy outcomes (APOs), but causal relationships remain unclear. This study aimed to investigate the relationship between genetically predicted biological aging traits and APOs. Genetic summary statistics from the genome-wide association study (GWAS) of the IEU open GWAS, FinnGen, and meta-analysis were analyzed using Mendelian randomization (MR) to infer causality. Biological aging indicators included facial aging, frailty index, and epigenetic aging markers. APOs included gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HTP), preterm birth (PTB), and pregnancy loss (PL). The primary MR analyses utilized the inverse variance weighted method, followed by sensitivity analyses. Reverse MR and multivariable MR were employed to explore reverse causality and potential mediating effects. We found that the frailty index was positively associated with GDM (OR = 2.00, 95% CI 1.44-2.77, P = 3.41E - 5), HTP (OR = 2.09, 95% CI 1.33-3.29, P = 0.001), and PL (OR = 1.22, 95% CI 1.03-1.46, P = 0.023) risks. Inverse MR showed that susceptibility to HTP (β = 0.05, 95% CI 0.03-0.07, P = 4.43E - 6) and PL (β = 0.06, 95% CI 0.01-0.11, P = 0.011) was positively correlated with the frailty index, while PTB was positively correlated with PhenoAge (β = 0.24, 95% CI 0.02-0.46, P = 0.035). Our findings suggest a genetic association between the frailty index and susceptibility to GDM, HTP, and PL. Closer monitoring of biological aging indicators during pregnancy may be necessary to prevent APOs.
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Affiliation(s)
- Ning Sun
- Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213000, China
| | - Kaiyan Yang
- Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213000, China
| | - Huihui Wang
- Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213000, China.
| | - Wenbo Zhou
- Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213000, China.
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Cecati M, Fumarola S, Vaiasicca S, Cianfruglia L, Vignini A, Giannubilo SR, Emanuelli M, Ciavattini A. Preeclampsia as a Study Model for Aging: The Klotho Gene Paradigm. Int J Mol Sci 2025; 26:902. [PMID: 39940672 PMCID: PMC11817256 DOI: 10.3390/ijms26030902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 01/18/2025] [Accepted: 01/20/2025] [Indexed: 02/16/2025] Open
Abstract
Aging and pregnancy are often considered opposites in a woman's biological timeline. Aging is defined by a gradual decline in the functional capabilities of an organism over its lifetime, while pregnancy is characterized by the presence of the transient placenta, which fosters the cellular fitness necessary to support fetal growth. However, in the context of preeclampsia, pregnancy and aging share common hallmarks, including clinical complications, altered cellular phenotypes, and heightened oxidative stress. Furthermore, women with pregnancies complicated by preeclampsia tend to experience age-related disorders earlier than those with healthy pregnancies. Klotho, a gene discovered fortuitously in 1997 by researchers studying aging mechanisms, is primarily expressed in the kidneys but also to a lesser extent in several other tissues, including the placenta. The Klotho protein is a membrane-bound protein that, upon cleavage by ADAM10/17, is released into the circulation as soluble Klotho (sKlotho) where it plays a role in modulating oxidative stress. This review focuses on the involvement of sKlotho in the development of preeclampsia and age-related disorders, as well as the expression of the recently discovered Mytho gene, which has been associated with skeletal muscle atrophy.
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Affiliation(s)
- Monia Cecati
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy;
| | - Stefania Fumarola
- Scientific Direction, IRCCS INRCA, 60124 Ancona, Italy; (S.F.); (S.V.); (L.C.)
| | - Salvatore Vaiasicca
- Scientific Direction, IRCCS INRCA, 60124 Ancona, Italy; (S.F.); (S.V.); (L.C.)
| | - Laura Cianfruglia
- Scientific Direction, IRCCS INRCA, 60124 Ancona, Italy; (S.F.); (S.V.); (L.C.)
| | - Arianna Vignini
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Università Politecnica Delle Marche, 60126 Ancona, Italy;
| | - Stefano Raffaele Giannubilo
- Department of Clinical Sciences, Clinic of Obstetrics and Gynaecology, Università Politecnica Delle Marche, 60123 Ancona, Italy;
| | - Monica Emanuelli
- Department of Clinical Sciences, Section of Biochemistry, Biology and Physics, Università Politecnica Delle Marche, 60126 Ancona, Italy;
| | - Andrea Ciavattini
- Department of Clinical Sciences, Clinic of Obstetrics and Gynaecology, Università Politecnica Delle Marche, 60123 Ancona, Italy;
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Alikhani F, Aalinezhad M, Bahrami M, Geravandi M. Placenta location, a prognostic determinant for the incidence of preeclampsia. BMC Pregnancy Childbirth 2024; 24:835. [PMID: 39707286 DOI: 10.1186/s12884-024-07050-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/09/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Preeclampsia is one of the complications of pregnancy with uncertain etiology. Nevertheless, it is believed that the condition may arise due to abnormal trophoblastic invasion, resulting in vascular remodeling and increased resistance in the spiral arteries. It is assumed that the location of the placenta might have contributed to the formation of trophoblastic invasion and further placental supply. The current study aims to investigate the association of placental location with the incidence of preeclampsia. METHODS The current case-control study was conducted on 206 primigravid pregnant woman undergone routine screening ultrasonography study between 14 and 26 gestational weeks to determine the location of the placenta (anterior, posterior, or lateral). The pregnant women were categorized as cases that met the criteria of high-risk for preeclampsia (n = 106) or the controls (n = 100). RESULTS Logistic regression analysis identified increased age (OR: 1.047, 95% CI: 1.02-1.07, PPP-value = 0.033), BMI > 25 kg/m² (OR: 4.61, 95% CI: 1.02-10.02, PPP-value = 0.038), and anterior placental location (OR: 2.79, 95% CI: 1.08-9.43, PPP-value = 0.038) as significant predictors of preeclampsia. Posterior placental location was initially associated with preeclampsia (PPP-value = 0.049), but this association was not robust and may reflect random variation. CONCLUSION This study identified anterior placental location, increased maternal age, and BMI above 25 kg/m² as significant predictors of preeclampsia. These findings suggest that healthcare providers should closely monitor pregnant women with anteriorly located placentas, advanced age, or elevated BMI. Regular blood pressure monitoring and urine protein screening for individuals with anterior placental location could facilitate early diagnosis and management of preeclampsia. While posterior placental location showed a potential association, it was less consistent, and further research is needed to confirm its role.
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Affiliation(s)
- Fariba Alikhani
- Department of Radiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marzieh Aalinezhad
- Department of Radiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahshid Bahrami
- Department of Radiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahsa Geravandi
- Department of Radiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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Yang Y, Chen M, Lan R, Gong H. LINC01410 accelerates the invasion of trophoblast cells by modulating METTL3/Fas. Mol Biol Rep 2024; 51:895. [PMID: 39115693 PMCID: PMC11310249 DOI: 10.1007/s11033-024-09834-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 07/30/2024] [Indexed: 08/11/2024]
Abstract
BACKGROUND Insufficient trophoblast invasion, culminating in suboptimal uterine spiral artery remodeling, is pinpointed as a pivotal contributor to preeclampsia (PE) development. LINC01410 has been documented to be increased in various neoplasms, and is significantly associated with the invasive capabilities of tumor cells. Nonetheless, its function and the mechanisms in the pathogenesis of PE require further investigation. METHODS AND RESULTS LINC01410 and methyltransferase-like 3 (METTL3) were ectopically expressed in HTR-8/Svneo cells via lentiviral transduction. Subsequently, the cells' invasive capabilities and apoptosis rates were evaluated employing Transwell assays and flow cytometry, respectively. The interplay between LINC01410 and METTL3, alongside the m6A methylation of FAS, was probed through RNA immunoprecipitation (RIP). Additionally, the association between FAS and METTL3 was elucidated via Coimmunoprecipitation (Co-IP) assays. The protein level of NF-κB, BAX, and BCL-2 in LINC01410-overexpressing cells was detected by Western blot. Our findings revealed that LINC01410 elevation increased the invasive ability of HTR-8/Svneo cells, directly impacting METTL3 then leading to its reduced expression. Conversely, heightened METTL3 expression mitigated invasiveness while enhancing apoptosis in these cells. Moreover, METTL3's interaction with FAS led to increased FAS expression, subject to m6A methylation. A surge in LINC01410 markedly decreased both mRNA and protein levels of FAS. Furthermore, LINC01410 overexpression significantly reduced NF-κB and BAX protein levels while augmenting BCL-2. CONCLUSIONS Upregulation of LINC01410 expression promotes trophoblast cell invasion by inhibiting FAS levels through modified m6A alteration and suppressing the NF-κB pathway. These findings underscore the pivotal role of LINC01410 in regulating trophoblast cell invasion and propose it as a promising therapeutic strategy for preventing or alleviating PE. This offers valuable insights for the clinical treatment of PE, for which definitive targeted therapy methods are currently lacking.
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Affiliation(s)
- Yang Yang
- Department of Obstetrics, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, 19 Xiu hua Road, Xiuying District, Haikou, Hainan, 570311, China
| | - Meihua Chen
- Hainan Medical University, 3 Xue yuan Road, Long hua District, Haikou, Hainan, 571199, China
| | - Ruihong Lan
- Department of Obstetrics, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, 19 Xiu hua Road, Xiuying District, Haikou, Hainan, 570311, China
| | - Humin Gong
- Department of Obstetrics, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, 19 Xiu hua Road, Xiuying District, Haikou, Hainan, 570311, China.
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O'Brien OM, Tremble SM, Kropf A, Cipolla MJ. Thrombin in Pregnancy and Preeclampsia: Expression, Localization, and Vasoactivity in Brain and Microvessels From Rats. J Cardiovasc Pharmacol 2024; 84:250-260. [PMID: 38922586 PMCID: PMC11402023 DOI: 10.1097/fjc.0000000000001579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 04/12/2024] [Indexed: 06/27/2024]
Abstract
ABSTRACT Thrombin is a coagulation factor increased in pregnancy and further increased in preeclampsia (PE), a hypertensive disorder. Thrombin is also expressed in the brain and may have a nonhemostatic role. We characterized thrombin expression and vasoactivity in brain cerebral parenchymal arterioles (PAs) in rat models of pregnancy and PE. PAs were isolated and pressurized from nonpregnant (NP) and late-pregnant (LP) rats and rats with experimental preeclampsia (ePE). Reactivity to thrombin (1-50 U/mL) was measured in the absence and presence of inhibition of cyclooxygenase and nitric oxide synthase. Plasma levels of prothrombin, thrombin-antithrombin (TAT), tissue plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1) and cerebrospinal fluid levels of TAT were compared using enzyme-linked immunosorbent assay. Expression of protease-activated receptor types 1 and 2 in PAs were measured by Western blot and immunohistochemistry. Neuronal thrombin expression was quantified in brains from all groups by immunohistochemistry. Prothrombin and TAT were elevated in ePE plasma compared with NP and LP. TAT was detected in cerebrospinal fluid from all groups and significantly elevated in LP (NP: 0.137 ± 0.014 ng/mL, LP: 0.241 ± 0.015 ng/mL, ePE: 0.192 ± 0.028 ng/mL; P < 0.05). Thrombin caused modest vasoconstriction in PAs from all groups regardless of cyclooxygenase or nitric oxide synthase inhibition. PAR1 and PAR2 were found in PAs from all groups colocalized to smooth muscle. Thrombin expression in central neurons was decreased in both LP and ePE groups compared with NP. These findings suggest a role for thrombin and other hemostatic changes during pregnancy and PE beyond coagulation.
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Affiliation(s)
- Olivia M O'Brien
- Department of Electrical and Biomedical Engineering, University of Vermont College of Engineering and Mathematical Sciences, Burlington, VT
- Department of Neurological Sciences, University of Vermont Larner College of Medicine, Burlington, VT
| | - Sarah M Tremble
- Department of Neurological Sciences, University of Vermont Larner College of Medicine, Burlington, VT
| | - Ari Kropf
- Department of Neurological Sciences, University of Vermont Larner College of Medicine, Burlington, VT
| | - Marilyn J Cipolla
- Department of Electrical and Biomedical Engineering, University of Vermont College of Engineering and Mathematical Sciences, Burlington, VT
- Department of Neurological Sciences, University of Vermont Larner College of Medicine, Burlington, VT
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont Larner College of Medicine, Burlington, VT; and
- Department of Pharmacology, University of Vermont Larner College of Medicine, Burlington, VT
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Ma F, Ding N, Xie L, Zhao X, Ma S, Li G, Hao Y, Xiong J, Wu K, Jiang Y, Zhang H. Inhibition of autophagy via 3-methyladenine alleviates the progression of preeclampsia. Acta Biochim Biophys Sin (Shanghai) 2024; 57:356-364. [PMID: 38978504 PMCID: PMC11986455 DOI: 10.3724/abbs.2024096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 05/27/2024] [Indexed: 07/10/2024] Open
Abstract
Autophagy is a cellular mechanism for self-renewal that involves the breakdown of cytoplasmic proteins or organelles within lysosomes. Although preeclampsia (PE) exhibits several characteristics that could imply disrupted autophagy, there is limited evidence supporting the notion that impaired placental autophagy directly causes PE, as indicated by differential expression profiling of whole placental tissue. In this study, we aim to explore the significance of autophagy in maintaining pregnancy and its association with PE. First, the RNA-seq results show that 218 genes are differentially expressed in placentas from preeclamptic pregnancies. Notably, KEGG pathway analysis reveals significant enrichment of genes related to autophagy-related signaling pathways, including the PI3K-Akt signaling pathway, the AMPK signaling pathway, and the mTOR signaling pathway. Additionally, our findings indicate an increase in autophagy in placentas from pregnancies complicated by preeclampsia as well as in trophoblasts subjected to hypoxic conditions. Next, we examine the impact of 3-methyladenine (3-MA), a targeted inhibitor of autophagy, on the progression of PE. The administration of 3-MA profoundly alleviates the severity of PE-like symptoms in rats subjected to reduced uterine perfusion pressure (RUPP). The findings from our study suggest that inhibiting autophagy may serve as a promising approach for adjuvant chemotherapy for PE.
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Affiliation(s)
- Fei Ma
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- School of Basic Medical SciencesNingxia Medical UniversityYinchuan750004China
| | - Ning Ding
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- School of Basic Medical SciencesNingxia Medical UniversityYinchuan750004China
| | - Lin Xie
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- School of Basic Medical SciencesNingxia Medical UniversityYinchuan750004China
| | - Xiangyu Zhao
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- School of Basic Medical SciencesNingxia Medical UniversityYinchuan750004China
| | - Shengchao Ma
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
| | - Guizhong Li
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- School of Basic Medical SciencesNingxia Medical UniversityYinchuan750004China
| | - Yinju Hao
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Department of Clinical MedicineNingxia Medical UniversityYinchuan750004China
- General Hospital of Ningxia Medical UniversityYinchuan750004China
| | - Jiantuan Xiong
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
| | - Kai Wu
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- School of Basic Medical SciencesNingxia Medical UniversityYinchuan750004China
| | - Yideng Jiang
- NHC Key Laboratory of Metabolic Cardiovascular Diseases ResearchNingxia Medical UniversityYinchuan750004China
- Ningxia Key Laboratory of Vascular Injury and Repair ResearchNingxia Medical UniversityYinchuan750004China
| | - Huiping Zhang
- Department of Medical GeneticsMaternal and Child Health of Hunan ProvinceChangsha410008China
- General Hospital of Ningxia Medical UniversityYinchuan750004China
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11
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Cao J, Jiang W, Yin Z, Li N, Tong C, Qi H. Mechanistic study of pre-eclampsia and macrophage-associated molecular networks: bioinformatics insights from multiple datasets. Front Genet 2024; 15:1376971. [PMID: 38846957 PMCID: PMC11153808 DOI: 10.3389/fgene.2024.1376971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 04/26/2024] [Indexed: 06/09/2024] Open
Abstract
Background Pre-eclampsia is a pregnancy-related disorder characterized by hypertension and proteinuria, severely affecting the health and quality of life of patients. However, the molecular mechanism of macrophages in pre-eclampsia is not well understood. Methods In this study, the key biomarkers during the development of pre-eclampsia were identified using bioinformatics analysis. The GSE75010 and GSE74341 datasets from the GEO database were obtained and merged for differential analysis. A weighted gene co-expression network analysis (WGCNA) was constructed based on macrophage content, and machine learning methods were employed to identify key genes. Immunoinfiltration analysis completed by the CIBERSORT method, R package "ClusterProfiler" to explore functional enrichment of these intersection genes, and potential drug predictions were conducted using the CMap database. Lastly, independent analysis of protein levels, localization, and quantitative analysis was performed on placental tissues collected from both preeclampsia patients and healthy control groups. Results We identified 70 differentially expressed NETs genes and found 367 macrophage-related genes through WGCNA analysis. Machine learning identified three key genes: FNBP1L, NMUR1, and PP14571. These three key genes were significantly associated with immune cell content and enriched in multiple signaling pathways. Specifically, these genes were upregulated in PE patients. These findings establish the expression patterns of three key genes associated with M2 macrophage infiltration, providing potential targets for understanding the pathogenesis and treatment of PE. Additionally, CMap results suggested four potential drugs, including Ttnpb, Doxorubicin, Tyrphostin AG 825, and Tanespimycin, which may have the potential to reverse pre-eclampsia. Conclusion Studying the expression levels of three key genes in pre-eclampsia provides valuable insights into the prevention and treatment of this condition. We propose that these genes play a crucial role in regulating the maternal-fetal immune microenvironment in PE patients, and the pathways associated with these genes offer potential avenues for exploring the molecular mechanisms underlying preeclampsia and identifying therapeutic targets. Additionally, by utilizing the Connectivity Map database, we identified drug targets like Ttnpb, Doxorubicin, Tyrphostin AG 825, and Tanespimycin as potential clinical treatments for preeclampsia.
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Affiliation(s)
- Jinfeng Cao
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
- Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Wenxin Jiang
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
- Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Zhe Yin
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
- Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Na Li
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
- Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Chao Tong
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hongbo Qi
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China
- Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
- Department of Obstetrics and Gynecology, Women and Children’s Hospital of Chongqing Medical University, Chongqing, China
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12
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Xie Y, Quan X, Yang X. Raised levels of chemerin in women with preeclampsia: A meta-analysis. BIOMOLECULES & BIOMEDICINE 2024; 24:454-464. [PMID: 37782564 PMCID: PMC11088885 DOI: 10.17305/bb.2023.9671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/12/2023] [Accepted: 09/30/2023] [Indexed: 10/04/2023]
Abstract
Chemerin is a multifunctional adipokine associated with systemic inflammation, angiogenesis, and oxidative stress. Emerging evidence suggests a potential link between chemerin and the pathogenesis of preeclampsia (PE). In this systematic review and meta-analysis, we aimed to evaluate the serum chemerin levels in women with PE. A systematic search was conducted across Medline, Web of Science, and Embase databases from inception until April 15, 2023, to identify studies comparing serum chemerin levels in pregnant women with and without PE. A random-effects model was employed to pool the results, accounting for heterogeneity. Thirteen datasets from 10 observational studies, encompassing 832 women with PE and 1298 healthy pregnant women, were analyzed. The pooled findings indicated a statistically significant elevation in serum chemerin levels in women with PE compared to controls (mean difference [MD] = 89.56 ng/mL, 95% confidence interval [CI] 62.14 - 116.98; P < 0.001; I2 = 87%). The subgroup analysis revealed consistent findings across studies that measured chemerin levels before or after the diagnosis of PE, studies that did or did not match the body mass index (BMI), and studies with varying quality scores (P values for subgroup differences were all > 0.05). Compared to controls, women with severe PE exhibited a significantly greater increase in serum chemerin levels than those with mild PE (P value for subgroup difference = 0.007). Additionally, meta-regression analysis results suggested that the mean BMI of the included pregnant women might positively modify the difference in circulating chemerin levels between women with and without PE (coefficient = 8.92; P = 0.045). In conclusion, this meta-analysis suggests a positive correlation between elevated serum chemerin levels and PE diagnosis in comparison to pregnant women without the condition.
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Affiliation(s)
- Yue Xie
- Department of Reproductive Center, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang City, Hubei Province, China
| | - Xiaozhen Quan
- Department of Reproductive Center, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang City, Hubei Province, China
| | - Xuezhou Yang
- Department of Reproductive Center, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang City, Hubei Province, China
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13
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Lan R, Yu Y, Song J, Xue M, Gong H. SFRP2 suppresses trophoblast cell migration by inhibiting the Wnt/β‑catenin pathway. Mol Med Rep 2024; 29:66. [PMID: 38426532 PMCID: PMC10926097 DOI: 10.3892/mmr.2024.13190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 01/16/2024] [Indexed: 03/02/2024] Open
Abstract
The present study investigates the role of Secreted Frizzled‑Related Protein 2 (SFRP2) in trophoblast cells, a key factor in preeclampsia (PE) progression. Elevated levels of Secreted Frizzled‑Related Protein 1/3/4/5 (SFRP1/3/4/5) are associated with PE, but the role of SFRP2 is unclear. We analyzed SFRP2 expression in PE placental tissue using the GSE10588 dataset and overexpressed SFRP2 in JEG‑3 cells via lentiviral transfection. The viability, migration, apoptosis, and proliferation of SFRP2‑overexpressing JEG‑3 cells were assessed using Cell Counting Kit‑8, Transwell assays, flow cytometry, and EdU staining. Additionally, we evaluated the impact of SFRP2 overexpression on key proteins in the Wnt/β‑catenin pathway and apoptosis markers (Bax, cleaved‑caspase 3, BCL‑2, MMP9, E‑cadherin, Wnt3a, Axin2, CyclinD1, c‑Myc, p‑β‑catenin, β‑catenin, phosphorylated Glycogen Synthase Kinase 3 beta (p‑GSK3β), and GSK3β) through western blotting. Results showed high SFRP2 mRNA and protein expression in PE placenta and JEG‑3 cells post‑transfection. SFRP2 overexpression significantly reduced JEG‑3 cell viability, proliferation, and migration, while increasing apoptosis. It also altered expression levels of Wnt pathway proteins, suggesting SFRP2's potential as a therapeutic target for PE by inhibiting trophoblast cell migration through the Wnt/β‑catenin signaling cascade.
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Affiliation(s)
- Ruihong Lan
- Department of Obstetrics, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, P.R. China
| | - Yihong Yu
- School of Clinical Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Jie Song
- Department of Obstetrics, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, P.R. China
| | - Mengdi Xue
- School of Clinical Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Humin Gong
- Department of Obstetrics, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, P.R. China
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14
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Shan Y, Hou B, Wang J, Chen A, Liu S. Exploring the role of exosomal MicroRNAs as potential biomarkers in preeclampsia. Front Immunol 2024; 15:1385950. [PMID: 38566996 PMCID: PMC10985148 DOI: 10.3389/fimmu.2024.1385950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/08/2024] [Indexed: 04/04/2024] Open
Abstract
The complex pathogenesis of preeclampsia (PE), a significant contributor to maternal and neonatal mortality globally, is poorly understood despite substantial research. This review explores the involvement of exosomal microRNAs (exomiRs) in PE, focusing on their impact on the protein kinase B (AKT)/hypoxia-inducible factor 1-α (HIF1α)/vascular endothelial growth factor (VEGF) signaling pathway as well as endothelial cell proliferation and migration. Specifically, this article amalgamates existing evidence to reveal the pivotal role of exomiRs in regulating mesenchymal stem cell and trophoblast function, placental angiogenesis, the renin-angiotensin system, and nitric oxide production, which may contribute to PE etiology. This review emphasizes the limited knowledge regarding the role of exomiRs in PE while underscoring the potential of exomiRs as non-invasive biomarkers for PE diagnosis, prediction, and treatment. Further, it provides valuable insights into the mechanisms of PE, highlighting exomiRs as key players with clinical implications, warranting further exploration to enhance the current understanding and the development of novel therapeutic interventions.
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Affiliation(s)
- Yuping Shan
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bo Hou
- Department of Cardiovascular Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jingli Wang
- Department of Medical Genetics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Aiping Chen
- Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shiguo Liu
- Department of Medical Genetics, The Affiliated Hospital of Qingdao University, Qingdao, China
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15
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Rich-Edwards JW. What twin pregnancies may tell us about associations of fertility and adverse pregnancy outcomes with long-term maternal health. Paediatr Perinat Epidemiol 2024; 38:227-229. [PMID: 38294095 DOI: 10.1111/ppe.13040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 12/28/2023] [Indexed: 02/01/2024]
Affiliation(s)
- Janet W Rich-Edwards
- Division of Women's Health, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
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16
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Medegan Fagla B, Buhimschi IA. Protein Misfolding in Pregnancy: Current Insights, Potential Mechanisms, and Implications for the Pathogenesis of Preeclampsia. Molecules 2024; 29:610. [PMID: 38338354 PMCID: PMC10856193 DOI: 10.3390/molecules29030610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/19/2024] [Accepted: 01/21/2024] [Indexed: 02/12/2024] Open
Abstract
Protein misfolding disorders are a group of diseases characterized by supra-physiologic accumulation and aggregation of pathogenic proteoforms resulting from improper protein folding and/or insufficiency in clearance mechanisms. Although these processes have been historically linked to neurodegenerative disorders, such as Alzheimer's disease, evidence linking protein misfolding to other pathologies continues to emerge. Indeed, the deposition of toxic protein aggregates in the form of oligomers or large amyloid fibrils has been linked to type 2 diabetes, various types of cancer, and, in more recent years, to preeclampsia, a life-threatening pregnancy-specific disorder. While extensive physiological mechanisms are in place to maintain proteostasis, processes, such as aging, genetic factors, or environmental stress in the form of hypoxia, nutrient deprivation or xenobiotic exposures can induce failure in these systems. As such, pregnancy, a natural physical state that already places the maternal body under significant physiological stress, creates an environment with a lower threshold for aberrant aggregation. In this review, we set out to discuss current evidence of protein misfolding in pregnancy and potential mechanisms supporting a key role for this process in preeclampsia pathogenesis. Improving our understanding of this emerging pathophysiological process in preeclampsia can lead to vital discoveries that can be harnessed to create better diagnoses and treatment modalities for the disorder.
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Affiliation(s)
| | - Irina Alexandra Buhimschi
- Department of Obstetrics and Gynecology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA;
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17
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Zhao X, Su F, Kong F, Su J, Yang X, Li L, Li A, Li Q. WD repeat domain 5 promotes the development of late-onset preeclampsia by activating nuclear factor kappa B. Acta Cir Bras 2023; 38:e386223. [PMID: 38055397 DOI: 10.1590/acb386223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 09/14/2023] [Indexed: 12/08/2023] Open
Abstract
PURPOSE Over-activation of nuclear factor kappa B (NF-κB) was proven to be involved in the pathogenesis of preeclampsia. However, its regulation mechanism is not clear yet. This paper explored the role of WD repeat domain 5 (WDR5) in the development of late-onset preeclampsia and its relationship with NF-κB. METHODS WDR5 expression was detected in normal placentas and placentas from late-onset preeclampsia patients. CCK-8 and colony formation assays were conducted to appraise the proliferative ability of trophoblast. Migration and invasion were observed by wound healing and transwell assays. The interaction between WDR5 and NF-κB inhibitor I-kappa-B-alpha (IkBa) was verified by Co-immunoprecipitation analysis. Immunofluorescence was used to analyze the activation of NF-κB. Finally, we tested the role of WDR5 using the mice late-onset preeclampsia model. RESULTS WDR5 was highly expressed in the placentas of late-onset preeclampsia patients. WDR5 overexpression suppressed cell proliferation, migration, and invasion in trophoblast. WDR5 could interact with IkBa to activate NF-κB. Knockdown of NF-κB counteracted the anti-proliferative and anti-metastatic effects of WDR5 overexpression in trophoblast. In-vivo studies suggested that targeting WDR5 combated late-onset preeclampsia development. CONCLUSIONS Our finding provides new insights into the role of WDR5 in late-onset preeclampsia development.
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Affiliation(s)
- Xudong Zhao
- Liaocheng People's Hospital - Department of Obstetrics and Gynaecology - Liaocheng (Shandong Province) - China
- The Affiliated Taian City Central Hospital of Qingdao University - Taian City Central Hospital - Department of Obstetrics - Taian City (Shandong Province) - China
| | - Fengyun Su
- The Second Affiliated Hospital of Shandong First Medical University - Second Affiliated Hospital - Department of Pharmacy - Taian City (Shandong Province) - China
| | - Fanhua Kong
- The Affiliated Taian City Central Hospital of Qingdao University - Taian City Central Hospital - Departments of Thoracic Surgery - Taian City (Shandong Province) - China
| | - Juan Su
- The Affiliated Taian City Central Hospital of Qingdao University , Taian City Central Hospital - Department of Obstetrics and Gynecology Color Ultrasound - Taian City (Shandong Province) - China
| | - Xiaojing Yang
- The Affiliated Taian City Central Hospital of Qingdao University - Taian City Central Hospital - Department of Obstetrics - Taian City (Shandong Province) - China
| | - Lei Li
- Shandong Provincial Hospital Affiliated to Shandong First Medical University - Shandong Provincial Hospital - Department of Obstetrics - Jinan City (Shandong Province) - China
| | - Aihua Li
- Liaocheng People's Hospital - Department of Obstetrics and Gynaecology - Liaocheng (Shandong Province) - China
| | - Qinwen Li
- The Affiliated Taian City Central Hospital of Qingdao University - Taian City Central Hospital - Department of Obstetrics - Taian City (Shandong Province) - China
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18
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DiBiase RM, Gottesman RF, Tom SE, Walker KA, Mosley T, Lutsey PL, Miller EC. Parity and Risk of Dementia in Women: The Atherosclerosis Risk in Communities Study. J Womens Health (Larchmt) 2023; 32:1031-1040. [PMID: 37615600 PMCID: PMC10541925 DOI: 10.1089/jwh.2023.0030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023] Open
Abstract
Objective: Reproductive factors, including parity, may contribute to dementia risk, due to hormonal, physiological, social, and demographic factors. We hypothesized that higher parity would be associated with increased dementia risk. Materials and Methods: We utilized data from the Atherosclerosis Risk in Communities (ARIC) community-based cohort study. Participants were recruited in 1987-1989 and followed through 2017. Participants, all born between 1921 and 1945, were from four U.S. communities in Forsyth County, NC; Jackson, MS; Minneapolis, MN; and Washington County, MD. We included all female participants seen at ARIC visit three or five for whom parity and dementia outcomes were available (N = 7,921). The primary exposure was self-reported number of live births. Our primary outcome was dementia, diagnosed via neurocognitive assessments, informant interviews, and expert adjudication. We created Cox proportional hazards models to evaluate the association between parity and incident dementia, adjusting for demographic factors, education level, apolipoprotein E allele status, and vascular risk factors. We tested for interactions by race and birth cohort. Results: The adjusted hazard ratio was 0.82 (95% confidence intervals [CI] 0.69-0.99) for dementia in women with 0-1 births and 0.85 (95% CI 0.72-0.99) for women with 5+ births, compared to women with 2 births (reference group). This association was present in women born from 1924 to 1934, but not in women born in 1935 or later (p-interaction <0.001). Conclusion: We found an inverted U-shaped association of parity with dementia risk. This effect was modified by birth cohort, suggesting that the association may depend on demographic and sociocultural factors.
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Affiliation(s)
- Rebecca M. DiBiase
- Department of Neurology, McGaw Medical Center of Northwestern University, Chicago, Illinois, USA
| | - Rebecca F. Gottesman
- Stroke Branch, National Institute of Neurological Disorders and Stroke Intramural Research Program, Bethesda, Maryland, USA
| | - Sarah E. Tom
- Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA
| | - Keenan A. Walker
- Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, Maryland, USA
| | - Thomas Mosley
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Pamela L. Lutsey
- Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota, USA
| | - Eliza C. Miller
- Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA
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19
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Liu Y, Gao J. Reproductive aging: biological pathways and potential interventive strategies. J Genet Genomics 2023; 50:141-150. [PMID: 35840100 DOI: 10.1016/j.jgg.2022.07.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 11/30/2022]
Abstract
Reproductive aging is a natural process conserved across species and is well-known in females. It shows age-related follicle depletion and reduction of oocyte quality, eventually causing reproductive senescence and menopause. Although reproductive aging in males is not well noticed as in females, it also causes infertility and has deleterious consequences on the offspring. Various factors have been suggested to contribute to reproductive aging, including oxidative stress, mitochondrial defects, telomere shortening, meiotic chromosome segregation errors and genetic alterations. With the increasing trend of pregnancy age, it is particularly crucial to find interventions to preserve or extend human fertility. Studies in humans and model organisms have provided insights into the biological pathways associated with reproductive aging, and a series of potential interventive strategies have been tested. Here, we review factors affecting reproductive aging in females and males and summarize interventive strategies that may help delay or rescue the aging phenotypes of reproduction.
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Affiliation(s)
- Yuanyuan Liu
- Center for Cell Structure and Function, College of Life Sciences, Key Laboratory of Animal Resistance Biology of Shandong Province, Shandong Normal University, Jinan, Shandong 250014, China
| | - Jinmin Gao
- Center for Cell Structure and Function, College of Life Sciences, Key Laboratory of Animal Resistance Biology of Shandong Province, Shandong Normal University, Jinan, Shandong 250014, China.
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20
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Abstract
Growth differentiation factor 15 (GDF-15) has been suggested as a potential biomarker of preeclampsia. However, previous studies evaluating circulating GDF-15 in women with preeclampsia showed inconsistent results. A meta-analysis was performed accordingly in this study. Observational studies comparing circulating GDF-15 between women with preeclampsia normal pregnancy were identified by search of electronic databases including PubMed, Embase, Web of Science, Wanfang, and CNKI. The Newcastle-Ottawa Scale (NOS) was used for assessing the quality of the studies. A randomized-effect model incorporating the possible between-study heterogeneity was used to pool the results. Eleven observational studies including 498 women with preeclampsia and 2349 women with normal pregnancy contributed to the meta-analysis. Results showed that compared to controls of women with normal pregnancy at least matched for gestational ages, women with preeclampsia had significantly higher circulating GDF-15 at the diagnosis [standard mean difference (SMD): 0.66, 95% confidence interval (CI): 0.16 to 1.17, p=0.01, I2=93%]. Subgroup analysis showed consistent results in women with preterm and term preeclampsia in Asian and non-Asian women and in studies with different quality scores, which were not statistically significant between subgroups (p for subgroup difference>0.05). Moreover, a higher level of GDF-15 was also found before the diagnosis in women who subsequently developed preeclampsia than those who did not (SMD: 1.32, 95% CI: 0.45 to 2.18, p=0.003, I2=89%). In conclusion, a higher circulating GDF-15 is observed in women with preeclampsia even before the diagnosis of the disease.
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Affiliation(s)
- Lihong Wang
- Department of Obstetrics and Gynecology, Baogang Hospital, Baotou, China
| | - Qiuli Yang
- Department of Obstetrics and Gynecology, Baogang Hospital, Baotou, China
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21
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Hypertensive disorders of pregnancy share common cfDNA methylation profiles. Sci Rep 2022; 12:19837. [PMID: 36400896 PMCID: PMC9674847 DOI: 10.1038/s41598-022-24348-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022] Open
Abstract
Hypertensive disorders of pregnancy (HDP) contribute substantially to perinatal morbidity and mortality. Epigenetic changes point towards cardio-metabolic dysregulation for these vascular disorders. In early pregnancy, epigenetic changes using cell free DNA (cfDNA) are largely unexplored. We aimed to investigate these in HDP between 11 and 14 weeks of gestation by analysis of cfDNA methylation profiles in patients with hypertensive disorders. We identified patients without chronic hypertension but with subsequent development of preeclampsia (PE) (n = 11), with chronic hypertension (HT) but without PE development (n = 14), and lacking both PE and HT (n = 422). We matched patients according to PE risk factors into three groups (n = 5 each group): (1) PE: no HT but PE development, (2) HT: chronic hypertension but no PE and (3) Control: no PE or HT. We successfully optimized our cfDNA isolation process prior to whole genome bisulfite sequencing. Analysis of cfDNA methylation changes indicate a common predisposition in PE and HT groups, chiefly of maternal origin. Assessment of significant differentially methylated regions and annotated genes point towards a common cardiovascular predisposition in preeclampsia and hypertension groups in the first trimester. We postulate the pivotal role of the maternal cardiovascular system in HDP, which is already evident in the first trimester.
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22
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Perišić MM, Vladimir K, Karpov S, Štorga M, Mostashari A, Khanin R. Polygenic Risk Score and Risk Factors for Preeclampsia and Gestational Hypertension. J Pers Med 2022; 12:1826. [PMID: 36579561 PMCID: PMC9694636 DOI: 10.3390/jpm12111826] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 10/23/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Preeclampsia and gestational hypertensive disorders (GHD) are common complications of pregnancy that adversely affect maternal and offspring health, often with long-term consequences. High BMI, advanced age, and pre-existing conditions are known risk factors for GHD. Yet, assessing a woman's risk of GHD based on only these characteristics needs to be reevaluated in order to identify at-risk women, facilitate early diagnosis, and implement lifestyle recommendations. This study demonstrates that a risk score developed with machine learning from the case-control genetics dataset can be used as an early screening test for GHD. We further confirm BMI as a risk factor for GHD and investigate a relationship between GHD and genetically constructed anthropometric measures and biomarkers. Our results show that polygenic risk score can be used as an early screening tool that, together with other known risk factors and medical history, would assist in identifying women at higher risk of GHD before its onset to enable stratification of patients into low-risk and high-risk groups for monitoring and preventative programs to mitigate the risks.
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Affiliation(s)
- Marija Majda Perišić
- LifeNome Inc., New York, NY 10018, USA
- Faculty of Mechanical Engineering and Naval Architecture, University of Zagreb, 10000 Zagreb, Croatia
| | - Klemo Vladimir
- LifeNome Inc., New York, NY 10018, USA
- Faculty of Electrical Engineering and Computing, University of Zagreb, 10000 Zagreb, Croatia
| | | | - Mario Štorga
- LifeNome Inc., New York, NY 10018, USA
- Faculty of Mechanical Engineering and Naval Architecture, University of Zagreb, 10000 Zagreb, Croatia
| | | | - Raya Khanin
- LifeNome Inc., New York, NY 10018, USA
- Bioinformatics Core, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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23
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Wang X, He A, Yip KC, Liu X, Li R. Diagnostic signature and immune characteristic of aging-related genes from placentas in Preeclampsia. Clin Exp Hypertens 2022; 44:1-8. [PMID: 36218052 DOI: 10.1080/10641963.2022.2130930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Preeclampsia (PE) is a serious pregnancy syndrome. Advanced maternal age (≥ 35 years old) is one of the major risk factors of PE and placental aging is considered to be related to this disease. However, the mechanisms underlying these phenomena remain obscured. METHODS Gene expression profiles of PE and non-PE placental samples were curated from the GSE75010 dataset. A diagnostic model was constructed and immune characteristics of PE subtypes were estimated. RESULTS A total of 58 aging-related genes, which may be associated with PE, were identified. Among them, LEP and FLT1 may be key aging-related genes. Based on 5 top genes (PIK3CB, FLT1, LEP, PIK3R1, CSNK1E), a diagnostic nomogram for PE was built (AUC = 0.872 in the GSE75010 dataset). Three molecular subtypes were clustered, which had different immune and angiogenesis characteristics. CONCLUSION The present study suggests the potential implications of aging-related genes in diagnosing PE. Diverse immune characteristics may be involved in the placental aging of PE.
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Affiliation(s)
- Xiufang Wang
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Andong He
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ka Cheuk Yip
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiaoting Liu
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ruiman Li
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Jinan University, Guangzhou, China
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Wang L, Zhang L, Fan Y, Peng Y, Song D, Fu J, Wang X. Human placenta-based genome-wide mRNA sequencing to identify TEK/IGF1/CSF1/ANGPT2 as crucial segments in the pathogenesis of pre-eclampsia. Front Genet 2022; 13:944932. [PMID: 36160014 PMCID: PMC9493102 DOI: 10.3389/fgene.2022.944932] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/16/2022] [Indexed: 11/24/2022] Open
Abstract
Pre-eclampsia is a pregnancy-specific disease commonly occurring in late pregnancy and has always been threatening maternal and fetal lives, yet the etiology and pathogenesis of pre-eclampsia are still uncertain. To depict the overall changes of genes at the genome-wide level and identify potential biomarkers for early diagnosis of pre-eclampsia, we conducted this study by collecting placenta samples donated by six pregnancy women, among whom three healthy women were included as controls and three women were diagnosed with pre-eclampsia. The placental sample tissues were then subjected to high-throughput sequencing. Furthermore, we proceeded with bioinformatics analysis and formulated the hypothesis of pre-eclampsia development and verified the potential targets of pre-eclampsia by immunohistochemistry. Demographically, we found that the baseline characteristics of study subjects were highly homogeneous except for gestational weeks and blood pressure, where the blood pressure was higher and gestational weeks were shorter in the pre-eclampsia group (systolic blood pressure 123.33 ± 4.62 vs. 148.67 ± 3.79 mmHg, p = 0.046; diastolic blood pressure 79.00 ± 5.20 vs. 88.33 ± 2.89 mmHg, p = 0.068; gestational weeks 39.33 ± 1.03 vs. 35.76 ± 2.41, p = 0.050). Specific pathological changes were identified, shown as syncytial knots, fibrinoid necrosis, perivillous fibrin deposition, and vasculitis. For high-throughput sequencing, a total of 1,891 dysregulated genes were determined, of which 960 genes were downregulated and 931 genes were upregulated. The bioinformatics analysis indicated that these genes, with different molecular functions in different parts of cells, were primarily responsible for endothelium development and vascular process in the circulatory system, and more than 10 signaling pathways were involved. By focusing on the PI3K-Akt signaling pathway, Rap1 signaling pathway, and disease enrichment analysis item pre-eclampsia, TEK, CSF1, IGF1, and ANGPT2 were identified to promote the development of pre-eclampsia. After confirming the placental expression of these genes at the protein level, we proposed the pathogenesis of pre-eclampsia as follows: the downregulation of TEK, CSF1, IGF1, and ANGPT2 may inhibit trophoblast proliferation and affect the remodeling of spiral arteries, causing maternal and fetal malperfusion and impeding nutrient exchange, thereby leading to clinical manifestations of pre-eclampsia.
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Affiliation(s)
- Lifeng Wang
- Obstetrical Department, Shandong Provincial Hospital, Shandong University, Jinan, China
- Obstetrical Department, Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province, Jinan, China
| | - Lin Zhang
- Clinical Medical Research Center for Women and Children Diseases, Maternal and Child Health Care Hospital of Shandong Province, Jinan, China
| | - Yuqin Fan
- Obstetrical Department, Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province, Jinan, China
| | - Yanjie Peng
- Clinical Medical Research Center for Women and Children Diseases, Maternal and Child Health Care Hospital of Shandong Province, Jinan, China
| | - Dandan Song
- Clinical Medical Research Center for Women and Children Diseases, Maternal and Child Health Care Hospital of Shandong Province, Jinan, China
| | - Jinfeng Fu
- Obstetrical Department, Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province, Jinan, China
| | - Xietong Wang
- Obstetrical Department, Shandong Provincial Hospital, Shandong University, Jinan, China
- Obstetrical Department, Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province, Jinan, China
- *Correspondence: Xietong Wang,
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Noren Hooten N, Brosh RM. Ageing Research Reviews Special Issue dedicated to women in aging research. Ageing Res Rev 2022; 77:101589. [PMID: 35158082 DOI: 10.1016/j.arr.2022.101589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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