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Eissa H, Abdelsalam EM, Mokbel SA, Elhadedy NH, Khalil RM, AbdElfattah AAM, Abdel Ghaffar DM, El Nashar EM, Hassan AH, Al-Zahrani NS, Aldahhan RA, Yassin NAE. Vitamin D supplementation as a prophylactic therapy in the management of pre-eclampsia: Focus on VEGF, Ki67, oxidative stress markers in correlation to placental ultra structure. Life Sci 2025; 372:123605. [PMID: 40194761 DOI: 10.1016/j.lfs.2025.123605] [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: 01/28/2025] [Revised: 03/21/2025] [Accepted: 04/01/2025] [Indexed: 04/09/2025]
Abstract
BACKGROUND Pre-eclampsia (PE) is a progressive hypertension condition that manifests in the second or third trimester of pregnancy and causes significant proteinuria. A lack of vitamin D (Vit. D) is linked to different pregnancy problems, including impaired placental development. Vitamin D has been shown to enhance fetal growth and lower the incidence of PE. AIM OF THE WORK To better understand the pathophysiological mechanisms behind the PE disease and the therapeutic approaches used to manage it, this study examines the role of Vit. D in placental ischemia and its regulatory effects in Nitro L-arginine Methyl Ester (L-NAME) animal model of PE. METHODS Fifty female rats in the estrus stage were mated with 30 male rats. Thirty female rats were pregnant and divided into three equal groups: control, Preeclampsia group (PE); using L-NAME for induction of PE, and Vit. D group from 7th day then induction by L-NAME at 10th day till end of pregnancy. Mean arterial Bp, proteinuria, oxidative stress markers, histological structure and immunohistochemical expression of Ki67 and VEGF, Morphometric study, and transmission electron microscopy(TEM) were assessed. The results of the current study suggested that, Vit. D supplementation could lower blood pressure, reduce oxidative stress, and restore angiogenic balance through vascular endothelial growth factor (VEGF) and Ki67. CONCLUSION For the first time, we conclude that vitamin D supplementation may not only have direct effects on blood pressure regulation and angiogenic hemostasis but also recover placental function, actually contributing to the prevention or management of PE.
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Affiliation(s)
- Hanan Eissa
- Department of Clinical Pharmacology, Mansoura University, Mansoura, Egypt.
| | | | - Somaia A Mokbel
- Department of Clinical Pharmacology, Mansoura University, Mansoura, Egypt.
| | - Nada H Elhadedy
- Department of Clinical Pathology, Mansoura University, Mansoura, Egypt
| | - Rania M Khalil
- Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
| | - Amany AbdElfattah Mohamed AbdElfattah
- Department of Medical Histology & Cell Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Department of Basic Medical Sciences, Faculty of Medicine, King Salman International University, South Sinai, Egypt.
| | - Dalia M Abdel Ghaffar
- Department of Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Eman Mohamad El Nashar
- Department of Anatomy, College Medicine, King Khalid University, Abha 62529, Saudi Arabia.
| | - Alshehri Hanan Hassan
- Endocrinology and Diabetes Section, Internal Medicine Department, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia.
| | - Norah Saeed Al-Zahrani
- Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia.
| | - Rashid A Aldahhan
- Department of Anatomy, College of Medicine, Imam Abdulrahman Bin Faisal University, P.O. Box 2114, Dammam 31451, Saudi Arabia.
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Jungelson A, Ridoux A, Barthe M, Redel D, Abbas H, Haddad B, Karumanchi SA, Lecarpentier E. Total and Free Placental Growth Factor Levels During Preeclampsia and Fetal Growth Restriction. Hypertension 2025; 82:883-893. [PMID: 40171652 DOI: 10.1161/hypertensionaha.125.24736] [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: 01/27/2025] [Accepted: 03/17/2025] [Indexed: 04/04/2025]
Abstract
BACKGROUND The objective of this study was to evaluate total circulating PlGF (placental growth factor) and free PlGF concentrations to provide insights into the mechanisms of decreased PlGF noted in preeclampsia and fetal growth restriction. METHODS We conducted a retrospective single-center study in pregnant women receiving care for suspected preeclampsia or fetal growth restriction. Serum angiogenic proteins (sFLT1 [soluble fms-like tyrosine kinase] and free PlGF) were measured on an automated platform as part of standard-of-care. Total PlGF concentrations in the serum were directly measured using a validated biochemical procedure that dissociated circulating sFLT1 and PlGF complexes. Small for gestational age (SGA) was defined by birthweight ≤10th percentile. RESULTS Of the 407 women studied, 155 women did not develop preeclampsia or SGA (control group), 111 women developed SGA without preeclampsia (SGA group), 71 women developed preeclampsia without SGA (preeclampsia group), and 70 developed preeclampsia and SGA (preeclampsia+SGA group). Despite reductions in free PlGF levels (229 [158-321] pg/mL), total PlGF levels were not reduced in the preeclampsia group (1020 [738-1444] pg/mL) compared with the control group (1077 [763-1595] pg/mL). In contrast, the total PlGF levels were significantly reduced in the SGA group (744 [462-1161] pg/mL; P<0.0001) and the preeclampsia +SGA group (616 [349-917] pg/mL; P<0.0001) compared with the control group (1077 [763-1595] pg/mL). CONCLUSIONS Placental dysfunction associated with preeclampsia, characterized by reduced free PlGF levels but unchanged total PlGF, is driven by excessive placental production of sFLT1. Placental dysfunction associated with SGA, marked by reductions in both free and total PlGF, is mediated by decreased placental PlGF production.
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Affiliation(s)
- Amélie Jungelson
- Service de Gynécologie Obstétrique, Centre Hospitalier Intercommunal de Créteil, France (A.J., D.R., B.H., E.L.)
| | - Audrey Ridoux
- Centre de Recherche Clinique du Centre Hospitalier Intercommunal de Créteil, Créteil, France (A.R., D.R.)
| | - Marion Barthe
- Institut Cochin, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique UMR8104, Faculté de Paris, France (M.B.)
| | - Diane Redel
- Service de Gynécologie Obstétrique, Centre Hospitalier Intercommunal de Créteil, France (A.J., D.R., B.H., E.L.)
- Centre de Recherche Clinique du Centre Hospitalier Intercommunal de Créteil, Créteil, France (A.R., D.R.)
| | - Houria Abbas
- Centre de Ressources Biologiques Centre Hospitalier Intercommunal de Créteil, France (H.A.)
| | - Bassam Haddad
- Service de Gynécologie Obstétrique, Centre Hospitalier Intercommunal de Créteil, France (A.J., D.R., B.H., E.L.)
- Faculté de Santé, Université Paris Est Créteil, France (B.H., E.L.)
| | - S Ananth Karumanchi
- Cedars-Sinai Medical Center, Department of Medicine, Los Angeles, CA (S.A.K.)
| | - Edouard Lecarpentier
- Service de Gynécologie Obstétrique, Centre Hospitalier Intercommunal de Créteil, France (A.J., D.R., B.H., E.L.)
- Faculté de Santé, Université Paris Est Créteil, France (B.H., E.L.)
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Mthembu MH, Sibiya S, Mlambo ZP, Mkhwanazi NP, Naicker T. Asymmetric Dimethylaminohydrolase Gene Polymorphisms Associated with Preeclampsia Comorbid with HIV Infection in Pregnant Women of African Ancestry. Int J Mol Sci 2025; 26:3271. [PMID: 40244094 PMCID: PMC11989882 DOI: 10.3390/ijms26073271] [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: 11/26/2024] [Revised: 03/26/2025] [Accepted: 03/27/2025] [Indexed: 04/18/2025] Open
Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor associated with vascular disease, which is prevalent in human plasma. Two isoforms of the enzyme dimethylarginine dimethylaminohydrolase (DDAH), DDAH 1 and 2, degrade ADMA. This study investigates the association of DDAH 1 (rs669173, rs7521189) and DDAH 2 gene polymorphisms (rs805305, rs3131383) with the risk of preeclampsia (PE) comorbidity with human immunodeficiency virus (HIV) infection in pregnant women of African ancestry. A total of 405 women were enrolled in this study: 204 were PE, 201 were normotensive pregnant, and 202 were HIV positive. DNA was extracted from whole blood, and SNPs (rs669173, rs7521189, rs805305, and rs3131383) were amplified to detect single-nucleotide polymorphisms (SNPs). After PCR amplification, allelic discrimination was examined. Comparisons were conducted utilizing the Chi-squared test. Our findings indicated that preeclamptic women displayed a greater prevalence of the three variants compared to those with both PE and HIV infection. There is an association between the rs669173 and rs7521189 SNPs of the DDAH 1 gene and rs3131383 of the DDAH 2 gene, which could play a role in reducing the bioavailability of nitric oxide (NO), which affects endothelial function, leading to the development of PE in pregnant women of African ancestry. In contrast, the rs805305 variant of the DDAH 2 gene was not significantly associated with PE development. Interestingly, none of the SNPs investigated correlated with HIV infection or could be attributed to the human allelic variant influence on HIV infection outcome.
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Affiliation(s)
- Mbuso Herald Mthembu
- Department of Obstetrics and Gynaecology, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4041, South Africa;
- Optics and Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Samukelisiwe Sibiya
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa; (S.S.); (N.P.M.)
| | - Zinhle Pretty Mlambo
- Optics and Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Nompumelelo P. Mkhwanazi
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa; (S.S.); (N.P.M.)
| | - Thajasvarie Naicker
- Optics and Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa;
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Zouganeli I, Moustakli E, Potiris A, Christodoulaki C, Arkoulis I, Kathopoulis N, Theofanakis C, Domali E, Panagopoulos P, Drakakis P, Stavros S. Genetic Variations in Vascular Endothelial Growth Factor and Their Impact on Preeclampsia: Insights into Risk, Severity, and Pregnancy Outcomes. Curr Issues Mol Biol 2025; 47:199. [PMID: 40136453 PMCID: PMC11941728 DOI: 10.3390/cimb47030199] [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: 02/15/2025] [Revised: 03/14/2025] [Accepted: 03/15/2025] [Indexed: 03/27/2025] Open
Abstract
Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and placental development, which are vital for a healthy pregnancy. Preeclampsia (PE), a hypertension condition that can cause major difficulties for both the mother and the fetus, has been linked to VEGF gene polymorphisms in several studies. PE susceptibility has been associated with several VEGF polymorphisms, including VEGF -2578C/A, -634G/C, +936C/T, and +405G/C, with differing outcomes in various ethnicities. Some polymorphisms, like VEGF -2578C/A, are linked to the disease's progression, whereas others, like VEGF +405G/C, may protect severe PE. The findings are still uncertain, though, with some studies reporting noteworthy outcomes and others finding no correlation. Further complicating our knowledge of VEGF's role in PE is the possibility that the interaction between maternal and fetal VEGF polymorphisms may affect PE risk. Studies on environmental variables and placental and fetal VEGF gene polymorphisms point to a complicated interaction in influencing the severity and susceptibility of PE. The precise genetic processes behind PE are still unknown, despite the mounting evidence, necessitating additional research to confirm possible biomarkers and treatment targets. In at-risk pregnancies, a better understanding of the connection between VEGF polymorphisms and PE may help with risk assessment and management techniques.
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Affiliation(s)
- Ioanna Zouganeli
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (I.Z.); (A.P.); (C.C.); (I.A.); (C.T.); (P.P.); (P.D.)
| | - Efthalia Moustakli
- Laboratory of Medical Genetics, Faculty of Medicine, School of Health Sciences, University of Ioannina, 451 10 Ioannina, Greece;
| | - Anastasios Potiris
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (I.Z.); (A.P.); (C.C.); (I.A.); (C.T.); (P.P.); (P.D.)
| | - Chrysi Christodoulaki
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (I.Z.); (A.P.); (C.C.); (I.A.); (C.T.); (P.P.); (P.D.)
| | - Ioannis Arkoulis
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (I.Z.); (A.P.); (C.C.); (I.A.); (C.T.); (P.P.); (P.D.)
| | - Nikolaos Kathopoulis
- First Department of Obstetrics and Gynecology, Alexandra Hospital, Medical School, National and Kapodistrian University of Athens, 115 28 Athens, Greece; (N.K.); (E.D.)
| | - Charalampos Theofanakis
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (I.Z.); (A.P.); (C.C.); (I.A.); (C.T.); (P.P.); (P.D.)
| | - Ekaterini Domali
- First Department of Obstetrics and Gynecology, Alexandra Hospital, Medical School, National and Kapodistrian University of Athens, 115 28 Athens, Greece; (N.K.); (E.D.)
| | - Periklis Panagopoulos
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (I.Z.); (A.P.); (C.C.); (I.A.); (C.T.); (P.P.); (P.D.)
| | - Peter Drakakis
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (I.Z.); (A.P.); (C.C.); (I.A.); (C.T.); (P.P.); (P.D.)
| | - Sofoklis Stavros
- Third Department of Obstetrics and Gynecology, University General Hospital “ATTIKON”, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (I.Z.); (A.P.); (C.C.); (I.A.); (C.T.); (P.P.); (P.D.)
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Racca AC, Nardi S, Flores-Martin J, Genti-Raimondi S, Panzetta-Dutari GM. KLF6 negatively regulates HIF-1α in extravillous trophoblasts under hypoxia. Placenta 2024; 156:38-45. [PMID: 39244791 DOI: 10.1016/j.placenta.2024.09.002] [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: 07/01/2024] [Revised: 08/21/2024] [Accepted: 09/04/2024] [Indexed: 09/10/2024]
Abstract
INTRODUCTION HIF-1α, the master regulator of hypoxia cellular response, is stabilized under low oxygen levels and degraded in the presence of oxygen but its transcription, translation, and degradation are tightly regulated by numerous pathways. KLF6 is a transcription factor involved in proliferation, differentiation, and apoptosis in several cell systems. Under hypoxia it is upregulated in a HIF-1α-dependent manner in extravillous trophoblasts. Considering the importance of hypoxia modulation of EVT behavior through HIF1-α we aimed to study whether KLF6 modulates HIF-1α expression in HTR8/SVneo cells. METHODS HTR8/SVneo cells were cultured in a 1 % oxygen chamber or in 3D format where a spontaneous oxygen gradient is generated. qRT-PCR and Western blot were performed to analyze mRNA and protein expression, respectively. SiRNA, shRNA, or plasmids were used to down- or up-regulate gene expression. Wound healing assay was performed under hypoxia to evaluate migration. The NFκB pathway was modulated with dominant negative mutants and a chemical inhibitor. Cobalt chloride was used to block HIF-1α degradation. RESULTS KLF6 up- and down-regulation in HTR8/SVneo cells exposed to acute hypoxia revealed a negative regulation on HIF-1α. KLF6 silencing led to a partially HIF-1α-dependent increase in MMP9 and VEGF. The NF-κB pathway and HIF-1α degradation were involved in KLF6-dependent HIF-1α regulation. HTR8/SVneo-3D culture showed that KLF6 negatively regulates HIF-1α in a microenvironment with naturally generated hypoxia. DISCUSSION Present results reveal that KLF6 contributes to a fine tune modulation of HIF-1α level under hypoxia. Thus, sustaining a HIF-1α homeostatic level, KLF6 might contribute to control EVT adaptation to hypoxia.
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Affiliation(s)
- Ana C Racca
- Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Ciudad Universitaria, X5000HUA, Córdoba, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Ciudad Universitaria, X5000HUA, Córdoba, Argentina.
| | - Sofía Nardi
- Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Ciudad Universitaria, X5000HUA, Córdoba, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Ciudad Universitaria, X5000HUA, Córdoba, Argentina
| | - Jésica Flores-Martin
- Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Ciudad Universitaria, X5000HUA, Córdoba, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Ciudad Universitaria, X5000HUA, Córdoba, Argentina
| | - Susana Genti-Raimondi
- Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Ciudad Universitaria, X5000HUA, Córdoba, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Ciudad Universitaria, X5000HUA, Córdoba, Argentina
| | - Graciela M Panzetta-Dutari
- Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Ciudad Universitaria, X5000HUA, Córdoba, Argentina; Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Ciudad Universitaria, X5000HUA, Córdoba, Argentina
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Mallawarachchi S, Cebecioglu RE, Althumayri M, Beker L, Fernando S, Ceylan Koydemir H. Systematic design and evaluation of aptamers for VEGF and PlGF biomarkers of Preeclampsia. BMC Biotechnol 2024; 24:64. [PMID: 39334133 PMCID: PMC11428563 DOI: 10.1186/s12896-024-00891-0] [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: 03/26/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
Preeclampsia is a potentially life-threatening condition for both mother and baby, characterized by hypertension and potential organ damage. Early diagnosis is crucial to mitigate its adverse health effects. Traditional diagnostic methods, which focus on late-manifesting symptoms like hypertension and proteinuria, underscore the need for molecular diagnostic approaches for timely detection. This study successfully designs and evaluates novel aptamers with high specificity and affinity for Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF), biomarkers closely associated with preeclampsia. Using molecular docking, molecular dynamics simulations, and BioLayer Interferometry (BLI), we identified aptamers that demonstrated strong binding affinities, comparable or superior to traditional antibodies. Our findings suggest that these aptamers have the potential to be integrated into cost-effective, point-of-care diagnostic tools, significantly improving early detection and intervention strategies for preeclampsia. The robust performance of these aptamers marks a pivotal step toward the development of more reliable and accessible diagnostic solutions, with implications for better maternal and fetal health outcomes.
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Affiliation(s)
- Samavath Mallawarachchi
- Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Rümeysa E Cebecioglu
- Department of Biomedical Sciences and Engineering, Koç University, Istanbul, 34450, Turkey
- Medical Laboratory Techniques, Health Services of Vocational School, Kent University, Istanbul, 34333, Turkey
| | - Majed Althumayri
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
- Center for Remote Health Technologies and Systems, Texas A&M Engineering Experiment Station, College Station, TX, 77843, USA
| | - Levent Beker
- Department of Mechanical Engineering, Koç University, Istanbul, 34450, Turkey
| | - Sandun Fernando
- Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Hatice Ceylan Koydemir
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA.
- Center for Remote Health Technologies and Systems, Texas A&M Engineering Experiment Station, College Station, TX, 77843, USA.
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Shabani M, Eghbali M, Abiri A, Abiri M. Comprehensive microarray analysis of severe preeclampsia placenta to identify differentially expressed genes, biological pathways, hub genes, and their related non-coding RNAs. Placenta 2024; 155:22-31. [PMID: 39121584 DOI: 10.1016/j.placenta.2024.08.003] [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: 07/03/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
INTRODUCTION Preeclampsia (PE) is a serious pregnancy-related complication caused by high blood pressure in pregnant women. The severe form has more devastating effects. According to the growing evidence, the placenta is a crucial component in the pathogenesis of PE, and eliminating it will alleviate symptoms. METHODS GEO's severe preeclampsia placenta microarray datasets; GSE147776, GSE66273, GSE102897, and GSE10588, were chosen to identify differentially expressed genes (DEGs) in different biological pathways. The analysis of hub genes and related non-coding RNAs was done as well. RESULTS A total of 347 DEGs with adj p-value <0.05 and ǀlog2FoldChangeǀ> 0.5 were discovered between severe PEs and healthy pregnancies, including 204 over-expressed genes and 143 under-expressed genes. The MCC method identified ISG15, IFI44L, MX2, OAS2, MX1, FN1, LDHA, ITGB3, TKT, HK2 genes as the top ten hub genes. Interactions between hub genes and noncoding RNAs were also conducted. The most enriched pathways were as follows; HIF-1 signaling pathway; Pathways in cancer; Alanine, aspartate and glutamate metabolism; Arginine biosynthesis; Human papillomavirus infection; Glycolysis/Gluconeogenesis; Central carbon metabolism in cancer; Valine, leucine and isoleucine degradation; Cysteine and methionine metabolism; and Galactose metabolism. DISCUSSION This is a secondary data analysis conducted on severe preeclampsia placenta to identify differentially expressed genes, biological pathways, hub-genes, and related noncoding RNAs. Functional studies are crucial to understanding the precise role of these genes in the pathogenesis of PE. Also, accepting a gene as a diagnostic or prognostic marker for early diagnosis and management of PE requires multiple lines of evidence.
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Affiliation(s)
- Maedeh Shabani
- Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Eghbali
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
| | - Ameneh Abiri
- Perinatology Department, Arash Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran.
| | - Maryam Abiri
- Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), Iran University of Medical Sciences, Tehran, Iran.
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Nema J, Sundrani D, Randhir K, Deshpande J, Lalwani S, Wagh G, Gupte S, Joshi S. Maternal angiogenic factor disruptions prior to clinical diagnosis of preeclampsia: insights from the REVAMP study. Hypertens Res 2024; 47:2532-2548. [PMID: 38965425 DOI: 10.1038/s41440-024-01775-8] [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: 12/12/2023] [Revised: 05/12/2024] [Accepted: 06/06/2024] [Indexed: 07/06/2024]
Abstract
Preeclampsia is characterized by impaired angiogenesis and assessment of angiogenic factors can play a crucial role in the early diagnosis of preeclampsia. The current study reports the levels of angiogenic factors longitudinally from early pregnancy in women with preeclampsia and in the subtypes of preeclampsia, to identify their role in early prediction of preeclampsia. A total of 1154 women with singleton pregnancies were recruited in early pregnancy from 2 hospitals. Blood samples were collected, plasma samples were separated and stored at four time points across gestation: V1 = 11-14 weeks, V2 = 18-22 weeks, V3 = 26-28 weeks, and V4 = at delivery. The current study includes a total of 108 women developed preeclampsia (PE), and 216 matched controls. Angiogenic factors were estimated using commercially available ELISA kits. Receiver operating characteristic (ROC) curves were used to evaluate the potential diagnostic value in the prediction of PE. Lower levels of VEGF, PlGF, and higher levels of sEng and sEng/PlGF ratio (p < 0.05 for all) predate clinical diagnosis in women with preeclampsia. sEng levels and sEng/PlGF ratio showed significant correlation with odds of preeclampsia at all the timepoints. This study identifies a cut off of 33.5 for sFlt-1/PlGF and 25.9 for sEng/PlGF for prediction of early onset preeclampsia. This study reports various angiogenic factors serially across gestation in a general population to identify women at risk of developing preeclampsia and its subtypes. The study also reports a potential biomarker and a pragmatic window for estimation of angiogenic markers to identify women at risk.
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Affiliation(s)
- Juhi Nema
- Mother and Child Health, ICMR- Collaborating Centre of Excellence (ICMR-CCoE), Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be University), Pune Satara Road, Pune, 411043, India
| | - Deepali Sundrani
- Mother and Child Health, ICMR- Collaborating Centre of Excellence (ICMR-CCoE), Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be University), Pune Satara Road, Pune, 411043, India
| | - Karuna Randhir
- Mother and Child Health, ICMR- Collaborating Centre of Excellence (ICMR-CCoE), Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be University), Pune Satara Road, Pune, 411043, India
| | - Juilee Deshpande
- Mother and Child Health, ICMR- Collaborating Centre of Excellence (ICMR-CCoE), Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be University), Pune Satara Road, Pune, 411043, India
| | - Sanjay Lalwani
- Department of Pediatrics, Bharati Medical College and Hospital, Bharati Vidyapeeth (Deemed to be University), Pune, 411043, India
| | - Girija Wagh
- Department of Obstetrics and Gynaecology, Bharati Medical College and Hospital, Bharati Vidyapeeth (Deemed to be University), Pune, 411043, India
| | - Sanjay Gupte
- Gupte Hospital and Research Centre, Pune, 411004, India
| | - Sadhana Joshi
- Mother and Child Health, ICMR- Collaborating Centre of Excellence (ICMR-CCoE), Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be University), Pune Satara Road, Pune, 411043, India.
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9
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Layman CE, Ward S, Davis BA, Nevonen KA, Okhovat M, Rincon M, Valent A, Carbone L, Thornburg KL. High-throughput methylome analysis reveals differential methylation for early and late onset preeclampsia for mothers and their children. Physiol Genomics 2024; 56:276-282. [PMID: 38189116 PMCID: PMC11283906 DOI: 10.1152/physiolgenomics.00058.2023] [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: 06/16/2023] [Revised: 11/14/2023] [Accepted: 01/04/2024] [Indexed: 01/09/2024] Open
Abstract
Preeclampsia is a hypertensive disorder of pregnancy that affects ∼2%-5% of all pregnancies, contributes to 4 of the top 10 causes of pregnancy-related deaths, and remains a long-term risk factor for cardiometabolic diseases. Yet, little is still known about the molecular mechanisms that lead to this disease. There is evidence that some cases have a genetic cause. However, it is well appreciated that harmful factors in the environment, such as poor nutrition, stress, and toxins, may lead to epigenetics changes that can contribute to this disease. DNA methylation is one of the epigenetic modifications known to be fairly stable and impact gene expression. Using DNA from buccal swabs, we analyzed global DNA methylation among three groups of individuals: mothers who experienced 1) early-stage preeclampsia (<32 wk), 2) late-stage preeclampsia (>37 wk), or 3) no complications during their pregnancies, as well as the children from these three groups. We found significant differentially methylated regions (DMRs) between mothers who experienced preeclampsia compared with those with no complications adjacent or within genes that are important for placentation, embryonic development, cell adhesion, and inflammation (e.g., the cadherin pathway). A significant portion of DMR genes showed expression in tissues relevant to preeclampsia (i.e., the brain, heart, kidney, uterus, ovaries, and placenta). As this study was performed on DNA extracted from cheek swabs, this opens the way to future studies in different tissues, aimed at identifying possible biomarkers of risk and early detection, developing targeted interventions, and reducing the progression of this life-threatening disease.NEW & NOTEWORTHY Preeclampsia is a life-threatening hypertensive disorder, affecting 2%-5% of pregnancies, that remains poorly understood. This study analyzed DNA methylation from buccal swabs from mothers who experienced early and late-stage preeclampsia and those with uncomplicated pregnancies, along with their children. Differentially methylated regions were found near and within genes crucial for placental function, embryonic development, and inflammation. Many of these genes are expressed in preeclampsia-related tissues, offering hope for future biomarker development for this condition.
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Affiliation(s)
- Cora E Layman
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States
| | - Samantha Ward
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States
| | - Brett A Davis
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States
| | - Kimberly A Nevonen
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States
| | - Mariam Okhovat
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States
| | - Monica Rincon
- Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon, United States
| | - Amy Valent
- Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon, United States
| | - Lucia Carbone
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, United States
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, Oregon, United States
- Division of Genetics, Oregon National Primate Research Center, Beaverton, Oregon, United States
| | - Kent L Thornburg
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States
- Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon, United States
- Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, Oregon, United States
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10
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Velegrakis A, Kouvidi E, Fragkiadaki P, Sifakis S. Predictive value of the sFlt‑1/PlGF ratio in women with suspected preeclampsia: An update (Review). Int J Mol Med 2023; 52:89. [PMID: 37594116 PMCID: PMC10500221 DOI: 10.3892/ijmm.2023.5292] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/13/2023] [Indexed: 08/19/2023] Open
Abstract
Preeclampsia (PE) is a major complication of pregnancy with an incidence rate of 2‑8% and is a leading cause of maternal mortality and morbidity. The various consequences of severe preeclampsia for the fetus, neonate and child include intrauterine growth retardation (IUGR), fetal hypoxia, oligohydramnios, intrauterine fetal demise, increased perinatal mortality and morbidity, neurodevelopmental disorders and even irreversible brain damage (cerebral palsy). A number of studies have demonstrated that differences in maternal serum concentrations of angiogenic factors between preeclampsia and normotensive pregnancies can be used as biomarkers, either alone or in combination with other markers, to predict the development of PE. The presence in the maternal circulation of two proteins of placental origin, placental growth factor (PlGF) and soluble fms‑like tyrosine kinase 1 (sFlt‑1), has been shown to be of clinical value, as the sFlt‑1/PlGF ratio appears to be the optimal predictive tool for the development of PE. The measurement of their concentration in maternal serum in screening models, serves as predictive marker for the development of PE or IUGR later in gestation. However, further research is required to improve its clinical applicability and provide guidelines for its use worldwide to achieve more consistent clinical management of women with PE.
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Affiliation(s)
- Alexandros Velegrakis
- Department of Obstetrics and Gynecology, University Hospital of Heraklion, 71500 Heraklion, Greece
| | - Elisavet Kouvidi
- Genesis Genoma Lab, Genetic Diagnosis, Clinical Genetics and Research, 15232 Athens, Greece
| | - Persefoni Fragkiadaki
- Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece
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11
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Suvakov S, Kattah AG, Gojkovic T, Enninga EAL, Pruett J, Jayachandran M, Sousa C, Santos J, Abou Hassan C, Gonzales-Suarez M, Garovic VD. Impact of Aging and Cellular Senescence in the Pathophysiology of Preeclampsia. Compr Physiol 2023; 13:5077-5114. [PMID: 37770190 DOI: 10.1002/cphy.c230003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
The incidence of hypertensive disorders of pregnancy is increasing, which may be due to several factors, including an increased age at pregnancy and more comorbid health conditions during reproductive years. Preeclampsia, the most severe hypertensive disorder of pregnancy, has been associated with an increased risk of future disease, including cardiovascular and kidney diseases. Cellular senescence, the process of cell cycle arrest in response to many physiologic and maladaptive stimuli, may play an important role in the pathogenesis of preeclampsia and provide a mechanistic link to future disease. In this article, we will discuss the pathophysiology of preeclampsia, the many mechanisms of cellular senescence, evidence for the involvement of senescence in the development of preeclampsia, as well as evidence that cellular senescence may link preeclampsia to the risk of future disease. Lastly, we will explore how a better understanding of the role of cellular senescence in preeclampsia may lead to therapeutic trials. © 2023 American Physiological Society. Compr Physiol 13:5077-5114, 2023.
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Affiliation(s)
- Sonja Suvakov
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Andrea G Kattah
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Tamara Gojkovic
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Elizabeth A L Enninga
- Division of Research, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Jacob Pruett
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Ciria Sousa
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Janelle Santos
- Division of Research, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Coline Abou Hassan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Vesna D Garovic
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Division of Research, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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12
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Rybak-Krzyszkowska M, Staniczek J, Kondracka A, Bogusławska J, Kwiatkowski S, Góra T, Strus M, Górczewski W. From Biomarkers to the Molecular Mechanism of Preeclampsia-A Comprehensive Literature Review. Int J Mol Sci 2023; 24:13252. [PMID: 37686054 PMCID: PMC10487701 DOI: 10.3390/ijms241713252] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/18/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Preeclampsia (PE) is a prevalent obstetric illness affecting pregnant women worldwide. This comprehensive literature review aims to examine the role of biomarkers and understand the molecular mechanisms underlying PE. The review encompasses studies on biomarkers for predicting, diagnosing, and monitoring PE, focusing on their molecular mechanisms in maternal blood or urine samples. Past research has advanced our understanding of PE pathogenesis, but the etiology remains unclear. Biomarkers such as PlGF, sFlt-1, PP-13, and PAPP-A have shown promise in risk classification and preventive measures, although challenges exist, including low detection rates and discrepancies in predicting different PE subtypes. Future perspectives highlight the importance of larger prospective studies to explore predictive biomarkers and their molecular mechanisms, improving screening efficacy and distinguishing between early-onset and late-onset PE. Biomarker assessments offer reliable and cost-effective screening methods for early detection, prognosis, and monitoring of PE. Early identification of high-risk women enables timely intervention, preventing adverse outcomes. Further research is needed to validate and optimize biomarker models for accurate prediction and diagnosis, ultimately improving maternal and fetal health outcomes.
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Affiliation(s)
| | - Jakub Staniczek
- Department of Gynecology, Obstetrics and Gynecological Oncology, Medical University of Silesia, 40-211 Katowice, Poland;
| | - Adrianna Kondracka
- Department of Obstetrics and Pathology of Pregnancy, Medical University of Lublin, 20-081 Lublin, Poland;
| | - Joanna Bogusławska
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland;
| | - Sebastian Kwiatkowski
- Department Obstetrics and Gynecology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Tomasz Góra
- Clinical Department of Gynecology and Obstetrics, Municipal Hospital, John Paul II in Rzeszów, 35-241 Rzeszów, Poland;
| | - Michał Strus
- Department of Obstetrics and Perinatology, University Hospital, 30-688 Krakow, Poland;
| | - Wojciech Górczewski
- Independent Public Health Care Facility “Bl. Marta Wiecka County Hospital”, 32-700 Bochnia, Poland;
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13
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Viana-Mattioli S, Fonseca-Alaniz MH, Pinheiro-de-Sousa I, Krieger JE, Sandrim VC. Missing links in preeclampsia cell model systems of endothelial dysfunction. Trends Mol Med 2023:S1471-4914(23)00073-4. [PMID: 37173223 DOI: 10.1016/j.molmed.2023.04.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 04/06/2023] [Accepted: 04/13/2023] [Indexed: 05/15/2023]
Abstract
Preeclampsia, one of the main hypertensive disorders of pregnancy, is associated with circulating factors released by the ischemic placenta accompanied by systemic endothelial dysfunction. The etiology of preeclampsia remains poorly understood although it is associated with high maternal and fetal mortality and increased cardiovascular disease risk. Most cell model systems used for studying endothelial dysfunction have not taken into account hemodynamic physical factors such as shear-stress forces which may prevent extrapolation of cell data to in vivo settings. We overview the role of hemodynamic forces in modulating endothelial cell function and discuss strategies to reproduce this biological characteristic in vitro to improve our understanding of endothelial dysfunction associated with preeclampsia.
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Affiliation(s)
- Sarah Viana-Mattioli
- Department of Biophysics and Pharmacology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, São Paulo, Brazil; Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, São Paulo, São Paulo, Brazil
| | - Miriam Helena Fonseca-Alaniz
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, São Paulo, São Paulo, Brazil
| | - Iguaracy Pinheiro-de-Sousa
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, São Paulo, São Paulo, Brazil; European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
| | - José Eduardo Krieger
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, São Paulo, São Paulo, Brazil
| | - Valéria Cristina Sandrim
- Department of Biophysics and Pharmacology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, São Paulo, Brazil.
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14
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Xu J, Zhou H, Zhou T, Guo Y, Liang S, Jia Y, Li K, Teng X. The impact of different endometrial preparation protocols on obstetric and neonatal complications in frozen-thawed embryo transfer: a retrospective cohort study of 3,458 singleton deliveries. Reprod Biol Endocrinol 2022; 20:141. [PMID: 36138458 PMCID: PMC9494872 DOI: 10.1186/s12958-022-01009-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 09/02/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Frozen-thawed embryo transfer (FET) is thought to be associated with obstetric and neonatal complications after in vitro fertilization/intracytoplasmic single sperm injection (IVF/ICSI) treatment. The study aimed to determine whether the endometrial preparation protocol is an influencing factor for these complications. METHODS We conducted a retrospective cohort study of 3,458 women who had singleton deliveries after IVF/ICSI-FET treatment at the Centre for Reproductive Medicine of Shanghai First Maternity and Infant Hospital between July 2016 and April 2021. The women were divided into three groups according to the endometrial preparation protocols: 2,029 women with programmed cycles, 959 with natural cycles, and 470 with minimal ovarian stimulation cycles. The primary outcomes were the incidence rates of obstetric and neonatal complications, namely, hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy (ICP), placenta previa, preterm rupture of membranes (PROM), preterm delivery, postpartum haemorrhage, large for gestational age (LGA), small for gestational age (SGA), and macrosomia. RESULTS After adjustments for confounding variables by multivariate logistic regression analysis, the results showed that programmed cycles had an increased risk of HDP (aOR = 1.743; 95% CI, 1.110-2.735; P = 0.016) and LGA (aOR = 1.269; 95% CI, 1.011-1.592; P = 0.040) compared with natural cycles. Moreover, programmed cycles also increased the risk of LGA (aOR = 1.459; 95% CI, 1.083-1.965; P = 0.013) but reduced the risk of SGA (aOR = 0.529; 95% CI, 0.348-0.805; P = 0.003) compared with minimal ovarian stimulation cycles. There were no significant differences between natural cycles and minimal ovarian stimulation cycles. CONCLUSIONS During IVF/ICSI-FET treatment, the risk of HDP and LGA was increased in women with programmed cycles. Therefore, for patients with thin endometrium, irregular menstruation or no spontaneous ovulation, minimal ovarian stimulation cycles may be a relatively safer option than programmed cycles.
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Affiliation(s)
- Junting Xu
- Centre for Reproductive Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Hong Zhou
- Centre for Reproductive Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Tianfan Zhou
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yi Guo
- Centre for Reproductive Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Shanshan Liang
- Centre for Reproductive Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yanping Jia
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Kunming Li
- Centre for Reproductive Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
| | - Xiaoming Teng
- Centre for Reproductive Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
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15
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Quintanilha JCF, Hammond K, Liu Y, Marmorino F, Borelli B, Cremolini C, Nixon AB, Innocenti F. Plasma levels of VEGF-A and VCAM-1 as predictors of drug-induced hypertension in patients treated with VEGF-pathway inhibitors. Br J Clin Pharmacol 2022; 88:4171-4179. [PMID: 35437784 DOI: 10.1111/bcp.15356] [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: 01/14/2022] [Revised: 03/14/2022] [Accepted: 04/11/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Hypertension is a common toxicity induced by vascular endothelial growth factor (VEGF)-pathway inhibitors. There are no validated markers of hypertension induced by these drugs. EXPERIMENTAL APPROACH We previously discovered that cancer patients with lower plasma levels of angiopoietin-2, VCAM-1, and VEGF-A are at high risk of developing severe hypertension when treated with bevacizumab. This study aimed to validate the predictive value of these markers in pretreatment plasma samples of an additional cohort of 101 colorectal cancer patients treated with regorafenib. The levels of angiopoietin-2, VCAM-1, and VEGF-A were measured by ELISA. The association between proteins and grade ≥2 regorafenib-induced hypertension was performed by calculating the odds ratio (OR) from logistic regression. Using the optimal cut-point of each protein, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for hypertension were estimated. KEY RESULTS Lower levels of VCAM-1 (p=0.015, OR=3.11, 95% CI 1.27-8.08) and VEGF-A (p=0.007, OR=3.47, 95% CI 1.40-8.75) were associated with a higher risk of hypertension. Levels of angiopoietin-2 were not associated with hypertension. The multivariable model indicates an independent effect of VCAM-1 (p=0.018, OR=3.18, 95% CI 1.25-8.68) and VEGF-A (p=0.008, OR=3.77, 95% CI 1.44-10.21). The presence of low levels of both VCAM-1 and VEGF-A had an OR of 9.46 (95% CI 3.08-33.26, p=1.70x10-4 ) for the risk of hypertension (sensitivity of 41.4%, specificity of 93.1%, PPV of 70.6% and NPV of 79.8%). CONCLUSION AND IMPLICATIONS This study confirmed the value of VCAM-1 and VEGF-A levels in predicting hypertension induced by regorafenib, another VEGF-pathway inhibitor.
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Affiliation(s)
- Julia C F Quintanilha
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Kelli Hammond
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Yingmiao Liu
- Duke University School of Medicine, Duke University, Durham, North Carolina, USA
| | - Federica Marmorino
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.,Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Beatrice Borelli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.,Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.,Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Andrew B Nixon
- Duke University School of Medicine, Duke University, Durham, North Carolina, USA
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16
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Plasma levels of angiopoietin-2, VEGF-A, and VCAM-1 as markers of bevacizumab-induced hypertension: CALGB 80303 and 90401 (Alliance). Angiogenesis 2022; 25:47-55. [PMID: 34028627 PMCID: PMC8611102 DOI: 10.1007/s10456-021-09799-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 05/15/2021] [Indexed: 02/03/2023]
Abstract
Hypertension is a common toxicity induced by bevacizumab and other antiangiogenic drugs. There are no biomarkers to predict the risk of bevacizumab-induced hypertension. This study aimed to identify plasma proteins related to the function of the vasculature to predict the risk of severe bevacizumab-induced hypertension. Using pretreated plasma samples from 398 bevacizumab-treated patients in two clinical trials (CALGB 80303 and 90401), the levels of 17 proteins were measured via ELISA. The association between proteins and grade 3 bevacizumab-induced hypertension was performed by calculating the odds ratio (OR) from logistic regression adjusting for age, sex, and clinical trial. Using the optimal cut-point of each protein, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for hypertension were estimated. Five proteins showed no difference in levels between clinical trials and were used for analyses. Lower levels of angiopoietin-2 (p = 0.0013, OR 3.41, 95% CI 1.67-7.55), VEGF-A (p = 0.0008, OR 4.25, 95% CI 1.93-10.72), and VCAM-1 (p = 0.0067, OR 2.68, 95% CI 1.34-5.63) were associated with an increased risk of grade 3 hypertension. The multivariable model suggests independent effects of angiopoietin-2 (p = 0.0111, OR 2.71, 95% CI 1.29-6.10), VEGF-A (p = 0.0051, OR 3.66, 95% CI 1.54-9.73), and VCAM-1 (p = 0.0308, OR 2.27, 95% CI 1.10-4.92). The presence of low levels of 2-3 proteins had an OR of 10.06 (95% CI 3.92-34.18, p = 1.80 × 10-5) for the risk of hypertension, with sensitivity of 89.7%, specificity of 53.5%, PPV of 17.3%, and NPV of 97.9%. This is the first study providing evidence of plasma proteins with potential value to predict patients at risk of developing bevacizumab-induced hypertension.Clinical trial registration: ClinicalTrials.gov Identifier: NCT00088894 (CALGB 80303); and NCT00110214 (CALGB 90401).
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17
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Opichka MA, Rappelt MW, Gutterman DD, Grobe JL, McIntosh JJ. Vascular Dysfunction in Preeclampsia. Cells 2021; 10:3055. [PMID: 34831277 PMCID: PMC8616535 DOI: 10.3390/cells10113055] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/01/2021] [Accepted: 11/04/2021] [Indexed: 01/22/2023] Open
Abstract
Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.
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Affiliation(s)
- Megan A. Opichka
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (M.A.O.); (D.D.G.); (J.L.G.)
| | - Matthew W. Rappelt
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
| | - David D. Gutterman
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (M.A.O.); (D.D.G.); (J.L.G.)
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Justin L. Grobe
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (M.A.O.); (D.D.G.); (J.L.G.)
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Comprehensive Rodent Metabolic Phenotyping Core, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Jennifer J. McIntosh
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (M.A.O.); (D.D.G.); (J.L.G.)
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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18
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Kniotek M, Roszczyk A, Zych M, Wrzosek M, Szafarowska M, Zagożdżon R, Jerzak M. Sildenafil Citrate Downregulates PDE5A mRNA Expression in Women with Recurrent Pregnancy Loss without Altering Angiogenic Factors-A Preliminary Study. J Clin Med 2021; 10:jcm10215086. [PMID: 34768607 PMCID: PMC8584603 DOI: 10.3390/jcm10215086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/15/2021] [Accepted: 10/25/2021] [Indexed: 11/16/2022] Open
Abstract
In our previous study, we showed that sildenafil citrate (SC), a selective PDE5A blocker, modulated NK cell activity in patients with recurrent pregnancy loss, which correlated with positive pregnancy outcomes. It was found that NK cells had a pivotal role in decidualization, angiogenesis, spiral artery remodeling, and the regulation of trophoblast invasion. Thus, in the current study, we determined the effects of SC on angiogenic factor expression and production, as well as idNK cell activity in the presence of nitric synthase blocker L-NMMA. Methods: NK cells (CD56+) were isolated from the peripheral blood of 15 patients and 15 fertile women on MACS columns and cultured in transformation media containing IL-15, TGF-β, and AZA—a methylation agent—for 7 days in hypoxia (94% N2, 1% O2, 5% CO2). Cultures were set up in four variants: (1) with SC, (2) without SC, (3) with NO, a synthase blocker, and (4) with SC and NO synthase blocker. NK cell activity was determined after 7 days of culturing as CD107a expression after an additional 4h of stimulation with K562 erythroleukemia cells. The expression of the PDE5A, VEGF-A, PIGF, IL-8, and RENBP genes was determined with quantitative real-time PCR (qRT-PCR) using TaqMan probes and ELISA was used to measure the concentrations of VEGF-A, PLGF, IL-8, Ang-I, Ang-II, IFN–γ proteins in culture supernatants after SC supplementation. Results: SC downregulated PDE5A expression and had no effect on other studied angiogenic factors. VEGF-A expression was increased in RPL patients compared with fertile women. Similarly, VEGF production was enhanced in RPL patients’ supernatants and SC increased the concentration of PIGF in culture supernatants. SC did not affect the expression or concentration of other studied factors, nor idNK cell activity, regardless of NO synthase blockade.
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Affiliation(s)
- Monika Kniotek
- Department of Clinical Immunology, Medical University of Warsaw, 59 Nowogrodzka St., 02-006 Warsaw, Poland; (M.K.); (A.R.); (M.Z.); (R.Z.)
| | - Aleksander Roszczyk
- Department of Clinical Immunology, Medical University of Warsaw, 59 Nowogrodzka St., 02-006 Warsaw, Poland; (M.K.); (A.R.); (M.Z.); (R.Z.)
| | - Michał Zych
- Department of Clinical Immunology, Medical University of Warsaw, 59 Nowogrodzka St., 02-006 Warsaw, Poland; (M.K.); (A.R.); (M.Z.); (R.Z.)
| | - Małgorzata Wrzosek
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha St., 02-097 Warsaw, Poland;
- Laboratory of Biochemistry and Clinical Chemistry, Preclinical Research Center, Medical University of Warsaw, 1 Banacha St., 02-097 Warsaw, Poland
- Correspondence:
| | - Monika Szafarowska
- Department of Gynecology and Oncological Gynecology, Military Institute of Medicine, 128 Szaserów St., 04-141 Warsaw, Poland;
| | - Radosław Zagożdżon
- Department of Clinical Immunology, Medical University of Warsaw, 59 Nowogrodzka St., 02-006 Warsaw, Poland; (M.K.); (A.R.); (M.Z.); (R.Z.)
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, 59 Nowogrodzka St., 02-006 Warsaw, Poland
| | - Małgorzata Jerzak
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha St., 02-097 Warsaw, Poland;
- Laboratory of Biochemistry and Clinical Chemistry, Preclinical Research Center, Medical University of Warsaw, 1 Banacha St., 02-097 Warsaw, Poland
- m-CLINIC 77/U9 Pulawska St., 02-595 Warsawa, Poland
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Pereira MM, Mainigi M, Strauss JF. Secretory products of the corpus luteum and preeclampsia. Hum Reprod Update 2021; 27:651-672. [PMID: 33748839 PMCID: PMC8222764 DOI: 10.1093/humupd/dmab003] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 01/18/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Despite significant advances in our understanding of the pathophysiology of preeclampsia (PE), there are still many unknowns and controversies in the field. Women undergoing frozen-thawed embryo transfer (FET) to a hormonally prepared endometrium have been found to have an unexpected increased risk of PE compared to women who receive embryos in a natural FET cycle. The differences in risk have been hypothesized to be related to the absence or presence of a functioning corpus luteum (CL). OBJECTIVE AND RATIONALE To evaluate the literature on secretory products of the CL that could be essential for a healthy pregnancy and could reduce the risk of PE in the setting of FET. SEARCH METHODS For this review, pertinent studies were searched in PubMed/Medline (updated June 2020) using common keywords applied in the field of assisted reproductive technologies, CL physiology and preeclampsia. We also screened the complete list of references in recent publications in English (both animal and human studies) on the topics investigated. Given the design of this work as a narrative review, no formal criteria for study selection or appraisal were utilized. OUTCOMES The CL is a major source of multiple factors regulating reproduction. Progesterone, estradiol, relaxin and vasoactive and angiogenic substances produced by the CL have important roles in regulating its functional lifespan and are also secreted into the circulation to act remotely during early stages of pregnancy. Beyond the known actions of progesterone and estradiol on the uterus in early pregnancy, their metabolites have angiogenic properties that may optimize implantation and placentation. Serum levels of relaxin are almost undetectable in pregnant women without a CL, which precludes some maternal cardiovascular and renal adaptations to early pregnancy. We suggest that an imbalance in steroid hormones and their metabolites and polypeptides influencing early physiologic processes such as decidualization, implantation, angiogenesis and maternal haemodynamics could contribute to the increased PE risk among women undergoing programmed FET cycles. WIDER IMPLICATIONS A better understanding of the critical roles of the secretory products of the CL during early pregnancy holds the promise of improving the efficacy and safety of ART based on programmed FET cycles.
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Affiliation(s)
- María M Pereira
- Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Monica Mainigi
- Division of Reproductive Endocrinology and Infertility, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Centre for Research on Reproduction and Women’s Health, University of Pennsylvania, Philadelphia, PA,19104 USA
| | - Jerome F Strauss
- Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, 23298, USA
- Centre for Research on Reproduction and Women’s Health, University of Pennsylvania, Philadelphia, PA,19104 USA
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20
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Ruikar K, Aithala M, Shetty P, Dinesh US, Bargale A, Sadashiv R, Edachery Veedu S, Khode V, Neravi A, Patil P. Decreased expression of annexin A2 and loss of its association with vascular endothelial growth factor leads to the deficient trophoblastic invasion in preeclampsia. J Basic Clin Physiol Pharmacol 2021; 33:419-428. [PMID: 33878253 DOI: 10.1515/jbcpp-2020-0321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 01/30/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Preeclampsia (PE) remains the major cause for maternal and foetal mortality and morbidity. Invasion of endovascular trophoblast and remodelling of spiral artery are crucial actions of normal placental development. Non-fulfilment of these processes plays a leading role in the development of preeclampsia. Vascular endothelial growth factor (VEGF) is produced by extravillous trophoblastic tissue and decidual cell population is a well-known angiogenic growth which plays a fundamental role in placental pathogenesis of PE. Annexin A2 (ANXA2) is a profibrinolytic protein receptor required for plasminolysis, which is an important step in the formation of new blood vessel along with VEGF. Role of ANXA2 is poorly studied in context with human reproductive disease like preeclampsia. The purpose of the present study is to examine the expression and association of VEGF and ANXA2 in the term placentas of pregnancies with and without PE. METHODS The study group comprised of placental tissues procured from gestations with PE (n=30) and without (n=20) PE. The expression of VEGF and ANXA2 in the placental villous tissue was evaluated quantitatively by means of IHC, western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS Our IHC, western blotting and RT-PCR analysis illustrated the significant decrease in the expression of VEGF and ANXA2 in PE group compared with the normotensive control group (p<0.005). We observed statistically significant positive correlation among the expression of ANXA2 and VEGF in placentas of normotensive control group (p<0.0001). CONCLUSIONS The diminished expression of VEGF and ANXA2 in placenta may be associated with the defective angiogenesis and which may possibly play a vital role in PE pathogenesis.
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Affiliation(s)
- Komal Ruikar
- Department of Physiology, Shri BM Patil Medical College, Hospital & Research Centre, BLDE (Deemed to be University), Vijaypur, India.,Department of Physiology, SDM College of Medical Sciences & Hospital, Shri Dharmasthala Manjunatheshwara University, Dharwad, India
| | - Manjunatha Aithala
- Department of Physiology, Shri BM Patil Medical College, Hospital & Research Centre, BLDE (Deemed to be University), Vijaypur, India
| | - Praveenkumar Shetty
- Department of Biochemistry, K S Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, India.,Nitte University Centre for Science Education and Research, Mangalore, India
| | - Udupi Shastry Dinesh
- Department of Pathology, SDM College of Medical Sciences & Hospital Dharwad, Shri Dharmasthala Manjunatheshwara University,Dharwad, India
| | - Anil Bargale
- Department of Biochemistry, SDM College of Medical Sciences & Hospital, Shri Dharmasthala Manjunatheshwara University, Dharwad, India
| | - Roshni Sadashiv
- Department of Anatomy, SDM College of Medical Sciences & Hospital, Shri Dharmasthala Manjunatheshwara University,Dharwad, India
| | - Sarathkumar Edachery Veedu
- Department of Biochemistry, K S Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, India
| | - Vitthal Khode
- Department of Physiology, SDM College of Medical Sciences & Hospital, Shri Dharmasthala Manjunatheshwara University, Dharwad, India
| | - Asha Neravi
- Department of Obstetrics and Gynaecology, SDM College of Medical Sciences & Hospital, Shri Dharmasthala Manjunatheshwara University,Dharwad, India
| | - Prakash Patil
- Central Research Laboratory, K S Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, India
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21
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Deshpande JS, Sundrani DP, Sahay AS, Gupte SA, Joshi SR. Unravelling the potential of angiogenic factors for the early prediction of preeclampsia. Hypertens Res 2021; 44:756-769. [PMID: 33795844 DOI: 10.1038/s41440-021-00647-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/30/2020] [Accepted: 01/20/2021] [Indexed: 01/12/2023]
Abstract
Preeclampsia is a multisystem, multiorgan hypertensive disorder of pregnancy responsible for maternal and perinatal morbidity and mortality in low- and middle-income countries. The classic diagnostic features hold less specificity for preeclampsia and its associated adverse outcomes, suggesting a need for specific and reliable biomarkers for the early prediction of preeclampsia. The imbalance of pro- and antiangiogenic circulatory factors contributes to the pathophysiology of preeclampsia. Several studies have examined the profile of angiogenic factors in preeclampsia to search for a biomarker that will improve the diagnostic ability of preeclampsia and associated adverse outcomes. This may help in more efficient patient management and the reduction of associated health care costs. This article reviews the findings from previous studies published to date on angiogenic factors and suggests a need to apply a multivariable model from the beginning of pregnancy and continuing throughout gestation for the early and specific prediction of preeclampsia.
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Affiliation(s)
- Juilee S Deshpande
- Mother and Child Health, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be) University, Pune, India
| | - Deepali P Sundrani
- Mother and Child Health, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be) University, Pune, India
| | - Akriti S Sahay
- Mother and Child Health, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be) University, Pune, India
| | | | - Sadhana R Joshi
- Mother and Child Health, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be) University, Pune, India.
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22
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Vishnyakova P, Poltavets A, Nikitina M, Muminova K, Potapova A, Vtorushina V, Loginova N, Midiber K, Mikhaleva L, Lokhonina A, Khodzhaeva Z, Pyregov A, Elchaninov A, Fatkhudinov T, Sukhikh G. Preeclampsia: inflammatory signature of decidual cells in early manifestation of disease. Placenta 2021; 104:277-283. [PMID: 33472135 DOI: 10.1016/j.placenta.2021.01.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/28/2020] [Accepted: 01/08/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Preeclampsia is a pregnancy-specific complication characterized by hypertension in combination with proteinuria and/or various manifestations of multiple organ failure. It is believed that etiology of preeclampsia lies in dysfunction of the placenta and disorder of the maternal-fetal interactions. In preeclampsia decidual membrane, the maternal part of the placenta which normally supports immunological tolerance of the maternal organism to the semi-allogeneic fetus, becomes a site of inflammation. METHODS The aim of our study was to characterize the phenotype of decidual macrophages and plasma profiles in patients with late- and early-onset preeclampsia as compared with controls (n = 43). Decidual cells were obtained by enzymatic digestion method and characterized by flow cytometry analysis, real-time PCR, bioinformatics analysis, immunohistochemistry, and Western blot. Plasma samples were analyzed by multiplex assay. RESULTS The number of inflammation-associated CD86+ and CX3CR1+ cells was significantly higher in the early-onset preeclampsia while the portion of CD163+ cells was significantly higher among studied groups. We observed significant increase of endothelin-1 gene expression and a significant decrease in eNOS and GNB3 expression and TGFβ relative protein level in decidual cells of the early-onset preeclampsia samples. We also revealed elevation of pro- and anti-inflammatory cytokines in plasma of preeclampsia groups. DISCUSSION Our findings reflect profound early-onset preeclampsia-associated alterations in the decidua and emphasize the importance of the decidua as a link in the development of preeclampsia.
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Affiliation(s)
- P Vishnyakova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997, Moscow, Russia; Peoples' Friendship University of Russia (RUDN University), 117198, Moscow, Russia.
| | - A Poltavets
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997, Moscow, Russia
| | - M Nikitina
- Scientific Research Institute of Human Morphology, 117418, Moscow, Russia
| | - K Muminova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997, Moscow, Russia
| | - A Potapova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997, Moscow, Russia
| | - V Vtorushina
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997, Moscow, Russia
| | - N Loginova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997, Moscow, Russia
| | - K Midiber
- Scientific Research Institute of Human Morphology, 117418, Moscow, Russia
| | - L Mikhaleva
- Scientific Research Institute of Human Morphology, 117418, Moscow, Russia
| | - A Lokhonina
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997, Moscow, Russia; Peoples' Friendship University of Russia (RUDN University), 117198, Moscow, Russia
| | - Z Khodzhaeva
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997, Moscow, Russia
| | - A Pyregov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997, Moscow, Russia
| | - A Elchaninov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997, Moscow, Russia
| | - T Fatkhudinov
- Peoples' Friendship University of Russia (RUDN University), 117198, Moscow, Russia; Scientific Research Institute of Human Morphology, 117418, Moscow, Russia
| | - G Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named After Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997, Moscow, Russia
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Ren Z, Zhe D, Li Z, Sun XP, Yang K, Lin L. Study on the correlation and predictive value of serum pregnancy-associated plasma protein A, triglyceride and serum 25-hydroxyvitamin D levels with gestational diabetes mellitus. World J Clin Cases 2020; 8:864-873. [PMID: 32190623 PMCID: PMC7062615 DOI: 10.12998/wjcc.v8.i5.864] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/06/2020] [Accepted: 02/09/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is a concern due to its rapid increase in incidence in recent years.
AIM To investigate the correlation and predictive value of serum pregnancy-associated plasma protein A (PAPP-A), triglyceride (TG), and 25-hydroxyvitamin D [25-(OH)D] with GDM in early pregnancy.
METHODS A total of 99 patients in early pregnancy admitted to Peking University International Hospital from November 2015 to September 2017 were included, and underwent a fasting glucose test and oral glucose tolerance test screening at 24-28 wk of pregnancy. Of these cases with GDM, 51 were assigned to group A and the remaining 48 cases without GDM were enrolled in group B. Serum PAPP-A, TG and 25-(OH)D in the two groups were compared and their correlation with blood sugar was analyzed. In addition, their diagnostic value in GDM was determined using receiver operating characteristic (ROC) curve analysis.
RESULTS Group A had markedly lower serum PAPP-A and 25-(OH)D levels and a significantly higher serum TG level than group B, with statistical significance (P < 0.05). Furthermore, Pearson analysis identified that PAPP-A and 25-(OH)D levels were negatively correlated with fasting blood glucose (FBG) levels (r = -0.605, P < 0.001), (r = -0.597, P < 0.001), while TG and FBG levels were positively correlated (r = 0.628, P < 0.001). The sensitivity, specificity, area under the curve (AUC) and optimal cut-off value of serum PAPP-A level in the diagnosis of GDM were 72.55%, 82.35%, 0.861 and 16.340, respectively, while the sensitivity of TG in diagnosing GDM was 86.27%, the specificity was 66.67%, the AUC was 0.813, with an optimal cut-off value of 1.796. The corresponding sensitivity, specificity, AUC and optimal cut-off value of serum 25-(OH)D were 64.71%, 70.59%, 0.721 and 23.140, respectively. Moreover, multivariate logistic regression analysis revealed that FBG, vascular endothelial growth factor, Flt-1, serum PAPP-A, TG, and 25-(OH)D were related risk factors leading to GDM in patients.
CONCLUSION Serum PAPP-A, TG, and 25-(OH)D levels are all correlated with blood glucose changes in GDM, and are independent factors affecting the occurrence of GDM and have certain value in the diagnosis of GDM.
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Affiliation(s)
- Zhuo Ren
- Department of Obstetrics and Gynecology, Peking University International Hospital, Beijing 102206, China
| | - Dong Zhe
- Department of Obstetrics and Gynecology, Peking University International Hospital, Beijing 102206, China
| | - Zhi Li
- Department of Obstetrics and Gynecology, Peking University International Hospital, Beijing 102206, China
| | - Xin-Ping Sun
- Department of Clinical Laboratory, Peking University International Hospital, Beijing 102206, China
| | - Kai Yang
- Department of Obstetrics and Gynecology, Peking University International Hospital, Beijing 102206, China
| | - Li Lin
- Department of Obstetrics and Gynecology, Peking University International Hospital, Beijing 102206, China
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Charkiewicz K, Goscik J, Raba G, Laudanski P. Syndecan 4, galectin 2, and death receptor 3 (DR3) as novel proteins in pathophysiology of preeclampsia. J Matern Fetal Neonatal Med 2019; 34:2965-2970. [PMID: 31608721 DOI: 10.1080/14767058.2019.1676410] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Preeclampsia has the highest rate of obstetric morbidity and mortality. METHODS We recruited 21 women with preeclampsia and 27 women with uncomplicated pregnancies. We used a quantitative protein macroarray that allowed for analysis of 40 proteins. RESULTS We found a statistically significant increase in the concentration of DR3, LIF and a significant decrease of VEGF, PlGF, syndecan-4 and galectin-2, in the plasma of women with preeclampsia. CONCLUSIONS There are no previous studies assessing syndecan 4, galectin 2, and DR3 concentrations in women with preeclampsia; Our results indicate these proteins are new factors that play important roles in the immunological pathomechanism of preeclampsia.
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Affiliation(s)
- Karol Charkiewicz
- Department of Perinatology and Obstetrics, Medical University of Bialystok, Białystok, Poland
| | - Joanna Goscik
- Faculty of Computer Science, Białystok University of Technology, Białystok, Poland
| | - Grzegorz Raba
- Institute of Obstetric and Emergency Medicine, University of Rzeszow, Żurawica, Poland
| | - Piotr Laudanski
- Department of Perinatology and Obstetrics, Medical University of Bialystok, Białystok, Poland.,Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland
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Venkata Surekha M, Singh S, Sarada K, Sailaja G, Balakrishna N, Srinivas M, Uday Kumar P. Study on the Effect of Severity of Maternal Iron Deficiency Anemia on Regulators of Angiogenesis in Placenta. Fetal Pediatr Pathol 2019; 38:361-375. [PMID: 31130046 DOI: 10.1080/15513815.2019.1587120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Aims: In this study, we hypothesized that maternal anemia leads to altered expression of angiogenic proteins vascular endothelial growth factor (VEGF), placental growth factor (PLGF), nitrotyrosine (NT) residues, and endothelial nitric oxide synthase (e-NOS) in the placenta. Hence, we study the expression of the abovementioned proteins in the placentas of mothers with different grades of anemia. Materials and methods: Our study was conducted in 48 pregnant women (36-40 weeks of gestation), who were divided into four groups-normal, mild, moderate, and severe anemia. After delivery, the expression of the angiogenic proteins was studied in their placentas by immunohistochemistry. Results: In our study, 58.3% of the pregnant women were anemic, among which 20.83% had mild anemia, 18.75% had moderate anemia, and 18.75% had severe anemia. Immunohistochemical staining intensity for VEGF, PLGF, NT residues, and e-NOS proteins was observed to be higher in the placentas of anemic women when compared with the non-anemic women. Conclusion: Our study showed that there is an increased expression of angiogenic proteins in the placentas of anemic mothers, which probably is an adaptive response leading to changes in placental vessels.
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Affiliation(s)
| | - Sapna Singh
- National Institute of Nutrition, Pathology Division , Tarnaka , Hyderabad, Telangana , India
| | - Krishnakumar Sarada
- National Institute of Nutrition, Pathology Division , Tarnaka , Hyderabad, Telangana , India
| | - Gummadi Sailaja
- National Institute of Nutrition, Pathology Division , Tarnaka , Hyderabad, Telangana , India
| | - Nagalla Balakrishna
- National Institute of Nutrition, Biostatistics , Tarnaka , Hyderabad, Telangana , India
| | - Myadara Srinivas
- National Institute of Nutrition, NCLAS , Tarnaka , Hyderabad, Telangana , India
| | - Putcha Uday Kumar
- National Institute of Nutrition, Pathology and Microbiology , Tarnaka , Hyderabad, Telangana , India
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Yu F, Bai Q, Zhang S, Jiang Y. Predictive value of soluble fms-like tyrosine kinase-1 against placental growth factor for preeclampsia in a Chinese pregnant women population. J Clin Lab Anal 2019; 33:e22861. [PMID: 30758082 PMCID: PMC6595471 DOI: 10.1002/jcla.22861] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 01/17/2019] [Accepted: 01/18/2019] [Indexed: 11/21/2022] Open
Abstract
Objective The purpose of the present study was to explore the predictive effects of soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF) for preeclampsia. Methods A total of 1580 singleton pregnant women aged 18‐45 years were included in this study. Serum samples were collected and stored frozen during their regular obstetric examinations. A total of 48 women who were eventually diagnosed with preeclampsia among them were defined as the preeclampsia group, other 134 women who were matched with age and sample collecting gestational weeks and finally diagnosed without preeclampsia were selected as control. The concentration of sFlt‐1 and PlGF in prestored serum samples was examined. The optimal cut‐off of sFlt‐1, PlGF, and sFlt‐1/PlGF ratio in predicting preeclampsia was determined by establishing the receiver operating characteristic curve (ROC). Results Serum PlGF levels in patients with preeclampsia were significantly lower than those in normal pregnancy (P < 0.05), On the contrary, sflt‐1 levels and sflt‐1/PlGF ratios were significantly higher than those in the normal pregnant women (P < 0.05). The ROC curve study showed that using the sFlt‐1/PlGF ratio to predict preeclampsia was better than using PlGF alone but no difference with sFlt‐1. When the cut‐off of the sFlt‐1/PlGF ratio was 26.6, the area under the ROC curve was 0.918, and high sensitivity (85.42%) and specificity (96.27%) for predicting preeclampsia were obtained. Conclusion The cut‐off of sflt‐1/PlGF ratio determined by ROC curve has a good predictive value for the occurrence of preeclampsia.
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Affiliation(s)
- Fan Yu
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Qianjin Bai
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Shihong Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.,Department of Gynaecology and Obstertrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yongmei Jiang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
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Beneficial effects of nicotinamide on the mouse model of preeclampsia. OA JOURNAL OF PREGNANCY AND CHILD CARE 2018; 1. [PMID: 34268502 PMCID: PMC8278325 DOI: 10.33118/oaj.preg.2019.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Preeclampsia (PE) is a pregnancy related disorder that is characterized by hypertension and proteinuria in the mother. It is associated with impaired coagulation and liver function, and a variety of other detrimental effects. In severe cases without treatment, PE can progress to eclampsia and result in seizures, a life-threatening condition. Although the etiology of PE is largely unknown, sFlt-1 (soluble vascular endothelial growth factor receptor 1) released by the impaired placenta resulting from insufficient perfusion plays a critical role in PE, and phenotypes of PE can be induced by experimentally increasing sFlt-1. We and other investigators have proposed that endothelin-1 (ET-1) system is the mediator of the pathological effects of excess sFlt-1, and antagonists of ET-1 receptor block the effects of sFlt-1. Unfortunately, this class of drugs is teratogenic and unsuitable for treating pregnant women. Nicotinamide is a naturally occurring derivative of vitamin B3 in the body and inhibits ADP-ribosyl cyclase, which is activated by the ET-1 receptor. Therefore, if utilized, it would be expected to play a beneficial role in PE. In mouse models of PE, a high dose of nicotinamide shows great success in lowering blood pressure, correcting renal function and structure, prolonging pregnancy as well as increasing fetal weight/number. Nicotinamide, being generally regarded as safe, could be a promising substance to further investigate for use in clinical trials.
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Sabriá E, Lequerica-Fernández P, Lafuente-Ganuza P, Eguia-Ángeles E, Escudero AI, Martínez-Morillo E, Barceló C, Álvarez FV. Addition of N-terminal pro-B natriuretic peptide to soluble fms-like tyrosine kinase-1/placental growth factor ratio > 38 improves prediction of pre-eclampsia requiring delivery within 1 week: a longitudinal cohort study. ULTRASOUND IN OBSTETRICS & GYNECOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY 2018; 51:758-767. [PMID: 29498431 DOI: 10.1002/uog.19040] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 01/19/2018] [Accepted: 02/19/2018] [Indexed: 06/08/2023]
Abstract
OBJECTIVE Short-term prediction of pre-eclampsia (PE) using the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio is characterized by frequent false-positive results. As such, no treatment can be recommended to test-positive patients and multiple measurements are often required. The aim of this study was to evaluate the effectiveness of N-terminal pro-B natriuretic peptide (NT-proBNP), uric acid and the sFlt-1/PlGF ratio for prediction of delivery with PE within 1 week in singleton pregnancies with suspected PE and sFlt-1/PlGF ratio > 38. METHODS This was a longitudinal prospective cohort study of singleton pregnancies presenting at 24 + 0 to 36 + 6 weeks of gestation with clinically suspected PE and sFlt-1/PlGF ratio > 38, enrolled between January 2015 and June 2017. Multiple samples per patient were allowed but were restricted to one sample per gestational week. From 495 enrolled patients, 270 blood samples from 134 patients were ultimately analyzed. By using generalized estimating equations (GEE), the best-fit model was selected for prediction of delivery with PE within 1 week. The predictive value of this model was then assessed using area under the paired-ROC curve (AUC) analysis. RESULTS The best-fit model included the sFlt-1/PlGF ratio, NT-proBNP and the gestational week at the time of the measurement. This combined model was compared with the GEE model based on the sFlt-1/PlGF ratio and the gestational week at the time of the measurement (reduced model). The AUC for the combined model was 0.845 (95% CI, 0.787-0.896), which was significantly greater (P = 0.011) than that of the reduced model (0.786 (95% CI, 0.722-0.844)). CONCLUSION The addition of NT-proBNP assessment improves the short-term prediction of delivery as a result of PE compared with sFlt-1/PlGF ratio alone, when the sFlt-1/PlGF ratio is > 38. This finding should be considered in future research on the assessment of short-term risk of delivery as a result of PE. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.
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Affiliation(s)
- E Sabriá
- Obstetrics and Gynaecology Department, Hospital-Residència Sant Camil, Barcelona, Spain
| | - P Lequerica-Fernández
- Biochemistry Department, Laboratory Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - P Lafuente-Ganuza
- Biochemistry Department, Laboratory Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - E Eguia-Ángeles
- Biochemistry Department, Laboratory Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - A I Escudero
- Obstetrics and Gynaecology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - E Martínez-Morillo
- Obstetrics and Gynaecology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - C Barceló
- Department of Computer Science and Applied Mathematics, Universitat de Girona, Girona, Spain
| | - F V Álvarez
- Biochemistry Department, Laboratory Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
- Department of Biochemistry and Molecular Biology, Universidad de Oviedo, Oviedo, Spain
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Dahabiyeh LA. The discovery of protein biomarkers in pre-eclampsia: the promising role of mass spectrometry. Biomarkers 2018; 23:609-621. [DOI: 10.1080/1354750x.2018.1474257] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Lina A. Dahabiyeh
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman, Jordan
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Charkiewicz K, Jasinska E, Goscik J, Koc-Zorawska E, Zorawski M, Kuc P, Raba G, Kluz T, Kalinka J, Sakowicz A, Laudanski P. Angiogenic factor screening in women with mild preeclampsia - New and significant proteins in plasma. Cytokine 2017; 106:125-130. [PMID: 29111087 DOI: 10.1016/j.cyto.2017.10.020] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 10/19/2017] [Accepted: 10/23/2017] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The aim of this study was to analyse a panel of 60 angiogenic factors (pro-angiogenic and antiangiogenic) in the plasma of women with mild preeclampsia. MATERIALS AND METHODS We recruited 21 women between 25 and 40 weeks gestation with diagnosed mild preeclampsia into the study group and 27 healthy women with uncomplicated pregnancies of corresponding gestational age to that of the study to the control group. We used a quantitative protein macroarray method that allowed for analysis of 60 angiogenic proteins per sample simultaneously. RESULTS We showed a statistically significant increase in the concentration of 8 proteins, interferon gamma (IFN-γ), interleukin 6 (IL-6), leukaemia inhibitory factor (LIF), heparin-binding EGF-like growth factor (HB-EGF), hepatocyte growth factor (HGF), C-X-C motif chemokine 10 (IP-10), leptin and platelet-derived growth factor BB (PDGF-BB), as well as a significant decrease in the concentration of 3 proteins, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and follistatin, in the plasma of women with preeclampsia. CONCLUSION Based on our findings, it seems that protein factors may play an important role in the pathogenesis of preeclampsia, and there are many proteins that have not been studied in PE to date. There are no previous studies assessing the LIF, follistatin, HGF, HB-EGF and PDGF-BB concentrations in the plasma of women with PE; therefore, our obtained results indicate that these proteins are new factors that can play an important role in the pathomechanisms of PE.
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Affiliation(s)
- Karol Charkiewicz
- Department of Perinatology and Obstetrics, Medical University of Bialystok, Marii Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland.
| | - Elwira Jasinska
- Department of Perinatology and Obstetrics, Medical University of Bialystok, Marii Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland
| | - Joanna Goscik
- Faculty of Computer Science, Bialystok University of Technology, Wiejska 45A, 15-351 Bialystok, Poland
| | - Ewa Koc-Zorawska
- Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Bialystok, Poland, Marii Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland
| | - Marcin Zorawski
- Department of Clinical Medicine, Medical University of Bialystok, Poland, Marii Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland
| | - Pawel Kuc
- Department of Perinatology and Obstetrics, Medical University of Bialystok, Marii Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland
| | - Grzegorz Raba
- Institute of Obstetric and Emergency Medicine, University of Rzeszow, Żurawica, 37-710 Podkarpackie, Poland
| | - Tomasz Kluz
- Department of Obstetrics and Gynecology, Fryderyk Chopin University Hospital No 1, Faculty of Medicine, Rzeszow University, Poland
| | - Jaroslaw Kalinka
- Department of Perinatology, Medical University of Lodz, 91-429 Lodz, Poland
| | - Agata Sakowicz
- Department of Medical Biotechnology, Medical University of Lodz, 91-425 Lodz, Poland
| | - Piotr Laudanski
- Department of Perinatology and Obstetrics, Medical University of Bialystok, Marii Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland.
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Montagnana M, Danese E, Lippi G, Fava C. Blood laboratory testing for early prediction of preeclampsia: chasing the finish line or at the starting blocks? Ann Med 2017; 49:240-253. [PMID: 27791388 DOI: 10.1080/07853890.2016.1255350] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Preeclampsia (PE) affects 2-8% of pregnancies worldwide, thus representing an important cause of maternal and neonatal morbidity, up to death. Many studies have been designed to identify putative biomarkers for accurate and timely diagnosing PE, but only some of them were focused on specific and sensitive biomarkers for early prediction of this life-threatening condition. In particular, some prospective studies aimed to investigate the predictive role of circulating biomarkers before 20 weeks of gestation in the general pregnant population yielded conflicting results. This article is hence centered on results obtained in studies investigating the predictive performances of angiogenic, anti-angiogenic, inflammatory, endocrine, and epigenetic biomarkers. The available evidence suggests that angiogenic and anti-angiogenic molecules, in particular the sFlt1:PlGF ratio, may be considered the biomarkers with the best diagnostic performance in the second trimester. However, doubts remain about their use in clinical settings before the 20th gestational week. Even lower evidence is available for other biomarkers, due to the fact that some positive results have not been confirmed in ensuing investigations, whereas unresolved analytical issues still contribute to make their clinical reliability rather questionable. Differential expression of microRNAs seems also a promising evidence for early prediction of PE, but additional research and well-designed prospective studies are needed to identify and validate routine predictive tests. KEY MESSAGES Preeclampsia affects 2-8% of pregnant women worldwide, thus remaining one of the leading causes of maternal and neonatal morbidity and mortality. Several studies have investigated the predictive role of circulating biomarkers before 20th week of gestation with conflicting results. Additional research and well-designed prospective studies are needed to identify and validate predictive tests in clinical practice.
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Affiliation(s)
- Martina Montagnana
- a Sezione di Biochimica Clinica, Dipartimento di Neuroscienze , Biomedicina e Movimento Università di Verona , Italy
| | - Elisa Danese
- a Sezione di Biochimica Clinica, Dipartimento di Neuroscienze , Biomedicina e Movimento Università di Verona , Italy
| | - Giuseppe Lippi
- a Sezione di Biochimica Clinica, Dipartimento di Neuroscienze , Biomedicina e Movimento Università di Verona , Italy
| | - Cristiano Fava
- b Sezione di Medicina Interna C, Dipartimento di Medicina , Università di Verona , Italy
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Reyna-Villasmil E, Mejia-Montilla J, Reyna-Villasmil N, Torres-Cepeda D, Santos-Bolívar J, Suárez-Torres I, Valencia-Rincón E. Concentraciones plasmáticas del factor de crecimiento vascular endotelial total en preeclampsia y eclampsia. CLINICA E INVESTIGACION EN GINECOLOGIA Y OBSTETRICIA 2017. [DOI: 10.1016/j.gine.2015.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Jammalamadaga VS, Abraham P. Spectrum of Factors Triggering Endothelial Dysfunction in PIH. J Clin Diagn Res 2017; 10:BC14-BC17. [PMID: 28208844 DOI: 10.7860/jcdr/2016/22113.9023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 08/24/2016] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Pre-eclampsia (PE) is a major cause of maternal and fetal/neonatal mortality and morbidity. The aetiology and pathogenesis of PE is yet to be completely understood. Evidence shows that, Endothelial Dysfunction (ED) plays a pivotal role in the genesis of this multi-system disorder that develops in PE and eclampsia. AIM To determine the circulating levels of factors Malondialdehyde (MDA), Ferric Reducing Ability of Plasma-α (FRAP), Tumour Necrosis Factor (TNF-α), sFlt-1, VEGF, PlGF, Nitric Oxide (NO) that influence the ED. MATERIALS AND METHODS Study groups consisted of Normotensive pregnant women (N), preeclamptic women (PE) and eclamptic women (E) with 100 subjects in each group in the 3rd trimester of pregnancy. They were investigated for MDA, FRAP, TNF-α, sFlt-1, VEGF, PlGF, NO. Statistical analysis was done using Analysis of Variance (ANOVA). RESULTS When compared to controls MDA, TNF-α, sFlt-1 levels were found to be significantly high and FRAP, VEGF, PIGF and NO levels were significantly low in PE and E group. E showed a significantly high level of MDA, TNF-α, sFlt-1 and low levels of FRAP, VEGF, PIGF, NO when compared to PE group. CONCLUSION Our study substantiated the fact, that oxidative stress, imbalance between anti-angiogenic factors and pro- angiogenic factors exists in Pregnancy Induced Hypertension (PIH) condition. This imbalance is directly related to the ED, the hallmark of PE. So oxidative stress, VEGF, PlGF and sFlt-1 can be used as markers to analyze the onset and progression of the disease.
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Affiliation(s)
- Visala Sree Jammalamadaga
- Research Scholar, Department of Biochemistry, Annapoorana Medical College and Hospital , Salem, Tamil Nadu, India
| | - Philips Abraham
- Associate Professor, Department of Biochemistry, Vinayaka Missions Kirupananda Variyar Medical College and Hospital , Salem, Tamil Nadu, India
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Tong M, Chen Q, James JL, Stone PR, Chamley LW. Micro- and Nano-vesicles from First Trimester Human Placentae Carry Flt-1 and Levels Are Increased in Severe Preeclampsia. Front Endocrinol (Lausanne) 2017; 8:174. [PMID: 28790977 PMCID: PMC5522845 DOI: 10.3389/fendo.2017.00174] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Accepted: 07/05/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND/OBJECTIVES Preeclampsia is a life-threatening hypertensive disease affecting 3-5% of pregnancies. While the pathogenesis of preeclampsia remains unclear, it is known that placenta-derived factors trigger the disease by activating maternal endothelial cells prior to the onset of clinical symptoms. Extracellular vesicles (EVs) of different sizes extruded by the placenta may be one factor. The truncated/secreted form of Flt-1 (sFlt-1) has also been implicated in the pathogenesis of preeclampsia. We investigated whether placental EV production is altered in preeclampsia such that they induce endothelial cell activation, and whether (s)Flt-1 is involved. METHODS Macro-, micro-, and nano-vesicles were collected from normal and preeclamptic (PE) placental explants, and separated by differential centrifugation. The number and size of micro- and nano-vesicles was measured by nanoparticle tracking analysis and their ability to activate endothelial cells was quantified by endothelial cell intercellular adhesion molecule 1 expression and monocyte adhesion. The levels of Flt-1 were measured by western blots and ELISA. RESULTS PE placentae extruded significantly more micro- and nano-vesicles than control placentae and the extruded micro-vesicles were larger than those from control placentae. Micro- and nano-vesicles from both first trimester and term human placentae carried Flt-1 and levels were significantly increased in EVs from severe, but not mild, PE compared to normotensive placentae. All fractions of EVs from PE placentae activated endothelial cells, and for micro- and nano-vesicles, activation was reduced in the presence of exogenous vascular endothelial growth factor (VEGF), a Flt-1 neutralizing antibody, or by pre-treatment with VEGF. While EV-bound VEGF constituted over 20% of the total detected VEGF secreted by PE and normotensive placentae, EV-bound Flt-1 did not significantly contribute to the total level of sFlt-1/Flt-1 released by human third trimester placentae. DISCUSSION Micro- and nano-vesicles extruded by human placentae carry Flt-1 across gestation and in severe preeclampsia, the levels of vesicle-bound Flt-1 are upregulated. All fractions of PE placental EVs activated endothelial cells and for micro- and nano-vesicles, this was in part due to the ability of EV-bound Flt-1 to sequester VEGF. That placental EVs can activate endothelial cells supports the contention that EVs are one placental toxin contributing to the pathogenesis of preeclampsia.
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Affiliation(s)
- Mancy Tong
- Department of Obstetrics and Gynaecology, School of Medicine, The University of Auckland, Auckland, New Zealand
- *Correspondence: Mancy Tong,
| | - Qi Chen
- Department of Obstetrics and Gynaecology, School of Medicine, The University of Auckland, Auckland, New Zealand
| | - Joanna L. James
- Department of Obstetrics and Gynaecology, School of Medicine, The University of Auckland, Auckland, New Zealand
| | - Peter R. Stone
- Department of Obstetrics and Gynaecology, School of Medicine, The University of Auckland, Auckland, New Zealand
| | - Lawrence W. Chamley
- Department of Obstetrics and Gynaecology, School of Medicine, The University of Auckland, Auckland, New Zealand
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Álvarez-Fernández I, Prieto B, Rodríguez V, Ruano Y, Escudero AI, Álvarez FV. N-terminal pro B-type natriuretic peptide and angiogenic biomarkers in the prognosis of adverse outcomes in women with suspected preeclampsia. Clin Chim Acta 2016; 463:150-157. [PMID: 27983995 DOI: 10.1016/j.cca.2016.10.033] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 10/27/2016] [Accepted: 10/27/2016] [Indexed: 10/20/2022]
Abstract
BACKGROUND This study compares the performance of the soluble fms-like tyrosine kinase 1 to placental growth factor (sFlt-1/PlGF) ratio and the cardiac biomarker N-terminal pro-B type natriuretic peptide (NT-proBNP) in the prediction of adverse outcomes in women with suspicion of PE. METHODS A retrospective cohort study was conducted on women admitted at triage with signs and/or symptoms of PE (n=340). Serum levels of sFlt-1, PlGF and NT-proBNP were determined by an electrochemiluminescence immunoassay (Roche Diagnostics). The main outcomes were early- or late-onset PE and development of adverse outcome, defined as delivery within the first week since clinical presentation or fetal/early neonatal death. RESULTS NT-proBNP concentrations (ng/L) were significantly increased in PE versus non-PE women, both at <34 (169 versus 34) and ≥34weeks of gestation (101 versus 49) (p<0.001). A cut-point of 70 showed sensitivities/specificities of 78/74% for early-, and 70/62% for late-onset PE; slightly lower than those offered by the sFlt-1/PlGF ratio or uric acid. The respective cut-points of 178 and 219 for sFlt-1/PlGF ratio and NT-proBNP, demonstrated similar performance in the prediction of adverse outcome, with sensitivity/specificity of 95/84% and 94/76%, respectively. CONCLUSION NT-proBNP and sFlt-1/PlGF ratio can be used to predict the development of an adverse outcome.
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Affiliation(s)
- Indira Álvarez-Fernández
- Clinical Biochemistry, Laboratory of Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Belén Prieto
- Clinical Biochemistry, Laboratory of Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain; Biochemistry and Molecular Biology Department, University of Oviedo, Spain
| | - Verónica Rodríguez
- Clinical Biochemistry, Laboratory of Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Yolanda Ruano
- Obstetric and Gynecology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ana I Escudero
- Obstetric and Gynecology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Francisco V Álvarez
- Clinical Biochemistry, Laboratory of Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain; Biochemistry and Molecular Biology Department, University of Oviedo, Spain.
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Teoh SSY, Zhao M, Wang Y, Chen Q, Nie G. Serum HtrA1 is differentially regulated between early-onset and late-onset preeclampsia. Placenta 2015; 36:990-5. [PMID: 26187609 DOI: 10.1016/j.placenta.2015.07.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 06/30/2015] [Accepted: 07/01/2015] [Indexed: 10/23/2022]
Abstract
INTRODUCTION HtrA1 (high temperature requirement A1) is a serine protease of the HtrA family. We have previously shown that the placenta expresses the highest level of HtrA1 mRNA compared to other tissues in the human. Others have reported that placental HtrA1 is significantly up-regulated in preeclampsia (PE), a pregnancy-specific multi-systemic disorder associated with new onset hypertension and proteinuria. However, it is unclear how serum HtrA1 changes in a normal pregnancy and whether it is altered in PE pregnancies. METHODS A sandwich ELISA highly specific to human HtrA1 and suitable for serum detection was developed and thoroughly validated. This assay was then applied to serum samples from different stages of normal pregnancy, as well as early-onset (<34 weeks) and late-onset (>34 weeks) PE pregnancies. RESULTS Serum HtrA1 increased progressively with increasing gestation in normal pregnancies. However, this trend was perturbed in women with PE. Compared to respective gestation-age-matched normal pregnancies, HtrA1 serum levels were significantly increased in early-onset PE, but significantly reduced in late-onset PE. DISCUSSION This is the first report to show a clear increase of HtrA1 in the maternal circulation during normal pregnancy, consistent with HtrA1 being highly expressed in the placenta. Importantly, this study identified that serum HtrA1 was altered differently in early-onset and late-onset PE pregnancies, highlighting the complex regulation of HtrA1 in the different subtypes. The significant increase of serum HtrA1 in early-onset PE suggests that it may be a potential biomarker for the diagnosis of early-onset PE at disease presentation.
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Affiliation(s)
- Sonia Soo Yee Teoh
- Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Monash University, Clayton, Victoria, Australia
| | - Min Zhao
- Wuxi Maternity and Children's Health Hospital, Nanjing Medical University, Jiangsu, PR China
| | - Yao Wang
- Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Monash University, Clayton, Victoria, Australia
| | - Qi Chen
- The Hospital of Obstetrics and Gynaecology, Fudan University, PR China; Department of Obstetrics and Gynaecology, The University of Auckland, New Zealand
| | - Guiying Nie
- Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Monash University, Clayton, Victoria, Australia.
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Promising prognostic markers of Preeclampsia: New avenues in waiting. Thromb Res 2015; 136:189-95. [DOI: 10.1016/j.thromres.2015.05.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 05/12/2015] [Accepted: 05/12/2015] [Indexed: 12/28/2022]
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Vinnars MT, Falkare S, Papadogiannakis N, Nasiell J. Placental pathology in smoking and non-smoking preeclamptic women. J Matern Fetal Neonatal Med 2015; 29:733-6. [PMID: 25716079 DOI: 10.3109/14767058.2015.1016421] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE To ascertain whether the protective effect of smoking during preeclampsia (PE) can be visualized in the placenta. METHODS The study cohort consisted of placentas (n = 523) from pregnancies complicated by PE, delivered at Karolinska University Hospital in Stockholm during the period 2000-2009. Of the women included in the study, 488 were non-smokers and 35 were smokers at first visit to maternity care. Outcome variables were placental infarctions and decidual arteriopathy. RESULTS Infarctions (affecting ≥5% of the placental tissue) were found in 15.6% of the placentas from non-smokers and in 25.7% of the placentas from smokers (OR 1.88: CI 0.84-4.16, p = 0.12). Decidual arteriopathy was found in 27.5% of the placentas from non-smokers and in 40.0% of the placentas from smokers (1.76: CI 0.87-3.56, p = 0.12). When diagnosed histopathologically, placental abruption was found in 15.4% among non-smokers and in 17.1% among smokers (1.14: CI 0.46-2.84, p = 0.98). Those differences did not show any statistical significance. CONCLUSION No significant differences concerning placental infarctions, decidual arteriopathy or abruption were found between preeclamptic placentas from non-smokers compared to smokers.
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Affiliation(s)
- Marie Therese Vinnars
- a Department of Clinical Science , Intervention and Technology, Division of Obstetrics and Gynecology, CLINTEC, Karolinska Institutet , Stockholm , Sweden .,b Örnsköldsviks Hospital , Örnsköldsvik , Sweden
| | - Sara Falkare
- a Department of Clinical Science , Intervention and Technology, Division of Obstetrics and Gynecology, CLINTEC, Karolinska Institutet , Stockholm , Sweden
| | - Nikos Papadogiannakis
- c Department of Laboratory Medicine , Division of Pathology, Karolinska Institutet , Stockholm , Sweden , and.,d Karolinska University Hospital , Stockholm , Sweden
| | - Josefine Nasiell
- a Department of Clinical Science , Intervention and Technology, Division of Obstetrics and Gynecology, CLINTEC, Karolinska Institutet , Stockholm , Sweden .,d Karolinska University Hospital , Stockholm , Sweden
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Procopciuc LM, Caracostea G, Zaharie G, Stamatian F. Maternal/newborn VEGF-C936T interaction and its influence on the risk, severity and prognosis of preeclampsia, as well as on the maternal angiogenic profile. J Matern Fetal Neonatal Med 2014; 27:1754-60. [PMID: 25007988 DOI: 10.3109/14767058.2014.942625] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE To analyze the influence of maternal/newborn vascular endothelial growth factor (VEGF)-CT936 interaction as a modulating factor in preeclampsia as well as its influence on the maternal angiogenic balance. METHODS Seventy pairs of preeclamptic women/newborns and 94 pairs of normal pregnant mothers/newborns were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum VEGF and soluble VEGF receptor-1 (sVEGFR-1) levels were measured using ELISA. RESULTS The risk to develop mild (odds ratio; OR: 3.79, p = 0.008) and severe (OR: 2.94, p = 0.037) preeclampsia being increased in association with the CT936-VEGF genotype and increased in severe preeclampsia to 6.07 (p = 0.03) if the women were carriers of the homozygous TT936-VEGF genotype. The presence of the VEGF-T936 allele in both the mother and the newborn significantly increases the risk of pregnancy-induced hypertension (PIH), mild and severe preeclampsia. If both the mothers and newborns were carriers of the VEGF-T936 allele, significantly lower VEGF and higher sVEGFR-1 levels were observed for all types of preeclampsia. Pregnant women with PIH and severe preeclampsia delivered at a significantly earlier gestational age neonates with a significantly lower birth weight if both the preeclamptic mothers and their newborns were carriers of the VEGF-T936 allele. CONCLUSIONS Our study suggests the role of maternal/fetal VEGF-CT936 polymorphism as a modulating factor in preeclampsia, which affects the angiogenic balance in preeclamptic mothers, as well as their pregnancy outcome.
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Abstract
Pregnancy-associated plasma protein A (PAPP-A) is a key regulator of insulin-like growth factor bioavailability essential for normal fetal development. In maternal blood, this protein increases with gestational age and then rapidly decreases after delivery. It is routinely used for Down syndrome screening in the first trimester of pregnancy, and its decrease compared to a normal pregnancy indicates an increased risk for both chromosomal anomalies and adverse pregnancy outcomes. It belongs to a group of biomarkers that predict later preeclampsia development, primarily early onset preeclampsia; however, it should be combined with a Doppler ultrasonography of the uterine artery (pulsatile index) and other biochemical and maternal factors to achieve a higher detection rate with an acceptable false positivity rate. Some studies have demonstrated an even more pronounced decrease of PAPP-A in the early second trimester of pregnancy in women who subsequently develop preeclampsia compared with women who do not develop preeclampsia. Conversely, during the last trimester of pregnancy, its concentration increases even more in patients with preeclampsia than in patients without. It is also detectable at very low levels in nonpregnant individuals, and a higher concentration indicates an adverse effect in patients with acute coronary syndromes or stable atherosclerotic disease and in patients with end-stage renal disease who are being treated with hemodialysis.
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Hadker N, Garg S, Costanzo C, van der Helm W, Creeden J. Are there financial savings associated with supplementing current diagnostic practice for preeclampsia with a novel test? Learnings from a modeling analysis from a German payer perspective. Hypertens Pregnancy 2014; 32:105-19. [PMID: 23725076 DOI: 10.3109/10641955.2011.638958] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE To quantify the financial impact of adding a novel serum test to the current diagnostic toolkit for preeclampsia (PE) detection in Germany. METHODS A decision-analytic model was created to quantify the economic impact of adding a recently developed novel diagnostic test for PE (Roche Diagnostics, Rotkreuz, Switzerland) to current diagnostic practice in Germany. The model simulated a cohort of 1000 pregnant patients receiving obstetric care and quantified the budget impact of adding the novel test to current German PE detection and management practices. RESULTS The model estimates that the costs associated with managing a typical pregnancy in Germany are €941 when the novel test is used versus €1579 with standard practice. This represents savings of €637 per pregnant woman, even when the test is used as a supplementary diagnostic tool. The savings are attributed to the novel test's ability to better classify patients relative to current practice, specifically, its ability to reduce false negatives by 67% and false positives by 71%. CONCLUSION The novel PE test has the potential to provide substantial cost savings to German healthcare payers, even when used as an addition to standard practice. Better classification of patients at risk for developing PE and declassification of those that are not compared to current practice leads to economic savings for the healthcare system. Furthermore, by reducing the rates of false-positive and false-negative classification relative to current standard of care, the test helps better target healthcare spending and lowers overall costs associated with PE care.
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Celik H, Avci B, Işik Y. Vascular endothelial growth factor and endothelin-1 levels in normal pregnant women and pregnant women with pre-eclampsia. J OBSTET GYNAECOL 2014; 33:355-8. [PMID: 23654314 DOI: 10.3109/01443615.2013.769944] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The aim of the study was to estimate the levels of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) in maternal serum from normal pregnant women and women with pre-eclampsia. Serum concentrations of VEGF and ET-1 were measured in maternal blood in control group (n = 40) and in pregnancies complicated by pre-eclampsia (n = 40). Results showed that maternal VEGF levels were significantly raised in women with pre-eclampsia (p < 0.001). ET-1 concentration was not significantly different among women with pre-eclampsia compared with that in the control group. It was concluded that an increase in serum VEGF level was demonstrated in pre-eclampsia, suggesting that VEGF is involved in pathogenesis of pre-eclampsia. Further studies are needed to determine the serum concentrations of VEGF in pregnant women before the development of pre-eclampsia.
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Affiliation(s)
- H Celik
- Department of Obstetrics and Gynecology, University of Ondokuz Mayis, School of Medicine, Kurupelit, Samsun.
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Free analyte QC concept: a novel approach to prove correct quantification of free therapeutic protein drug/biomarker concentrations. Bioanalysis 2014; 6:485-96. [DOI: 10.4155/bio.13.316] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Quantification of free drug concentrations is highly challenging due to the dynamic drug–ligand equilibrium, which may result in incorrect results. Current QC concepts do not adequately cover all of the important influencing factors: the assay itself (format and procedure); the calibration concept; the sample preparation; and the sample storage. Here, we propose a ‘free analyte QC concept’ that enables quantitative testing of these four factors and, thus, provides best possible proof of correct free drug quantification. The principle of the free analyte QC concept and an example of its application for a free drug assay is described. A comparison of this novel approach with current approaches and how the new concept fits (or does not fit) with current regulatory guidelines is discussed.
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Yi K, Jung S, Cho G, Seol H, Hong S, Oh M, Kim H. Effects of sFlt-1 and alpha 2-macroglobulin on vascular endothelial growth factor-induced endothelin-1 upregulation in human microvascular endothelial cells. Placenta 2014; 35:64-9. [DOI: 10.1016/j.placenta.2013.09.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 08/23/2013] [Accepted: 09/16/2013] [Indexed: 11/28/2022]
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Olmos A, Díaz L, Avila E, Barrera D, López-Marure R, Biruete B, Larrea F, Halhali A. Associations between insulin-like growth factor I, vascular endothelial growth factor and its soluble receptor 1 in umbilical serum and endothelial cells obtained from normotensive and preeclamptic pregnancies. Growth Factors 2013; 31:123-9. [PMID: 23750889 DOI: 10.3109/08977194.2013.802692] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The aim of this study was to investigate the associations between insulin-like growth factor I (IGF-I) with vascular endothelial growth factor (VEGF) and its soluble receptor 1 (sFlt-1) in umbilical serum and to study the effects of IGF-I upon sFlt-1 synthesis in human umbilical vein endothelial cells (HUVEC) in normotensive (NT) and preeclamptic (PE) pregnancies. As compared with the NT group, umbilical serum IGF-I and VEGF levels were lower in the PE group, while sFlt-1 concentrations were higher. Levels of sFlt-1 correlated with IGF-I in the NT group and with VEGF in the PE group. Basal concentration of sFlt-1 in HUVEC culture media was higher in the PE group. IGF-I stimulated sFlt-1 synthesis only in the NT group. In summary, umbilical serum sFlt-1 is associated with IGF-I in normotensive pregnancy and with VEGF in preeclampsia. IGF-I stimulates sFlt-1 synthesis in endothelial cells in normotensive but not in PE pregnancies.
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Affiliation(s)
- Andrea Olmos
- Department of Reproductive Biology Carlos Gual Castro, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, DF México
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Saito T, Takeda N, Amiya E, Nakao T, Abe H, Semba H, Soma K, Koyama K, Hosoya Y, Imai Y, Isagawa T, Watanabe M, Manabe I, Komuro I, Nagai R, Maemura K. VEGF-A induces its negative regulator, soluble form of VEGFR-1, by modulating its alternative splicing. FEBS Lett 2013; 587:2179-85. [PMID: 23711375 DOI: 10.1016/j.febslet.2013.05.038] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 04/28/2013] [Accepted: 05/09/2013] [Indexed: 01/10/2023]
Abstract
Vascular endothelial growth factor-A (VEGF-A) is one of the major angiogenic factors, and its actions are primarily mediated through its two membrane receptors, VEGFR-1 and VEGFR-2. A soluble form of VEGFR-1 (sVEGFR-1) sequesters the free form of VEGF-A, and acts as a potent anti-angiogenic factor. While sVEGFR-1 is synthesized as a splice variant of VEGF-R1 gene, the interactions between VEGF-A and sVEGFR-1 remain largely unknown. Here, we show that VEGF-A upregulates sVEGF-R1 expression in human vascular endothelial cells but leaves full-length VEGF-R1 expression unchanged, and that this induction was dependent on the VEGFR-2-protein kinase C-MEK signaling pathway. The VEGF-A-induced sVEGFR-1 upregulation can operate as a negative feedback system, which if modulated can become a novel therapeutic target for regulating pathological angiogenesis.
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Affiliation(s)
- Tetsuya Saito
- Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan
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Kim J, Cho S, Kim YJ, Park HS, Ha EH, Park EA. Cord Blood Soluble fms-Like Tyrosine Kinase 1 and Placental Growth Factor in Preterm Infants with Maternal Preeclampsia. THE EWHA MEDICAL JOURNAL 2013. [DOI: 10.12771/emj.2013.36.2.118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Jiyoung Kim
- Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea
| | - Sujin Cho
- Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea
| | - Young ju Kim
- Department of Obstetrics and Gynecology, Ewha Womans University School of Medicine, Seoul, Korea
| | - Hye Sook Park
- Department of Preventive Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Eun-Hee Ha
- Department of Preventive Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Eun Ae Park
- Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea
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Cross SN, Ratner E, Rutherford TJ, Schwartz PE, Norwitz ER. Bevacizumab-mediated interference with VEGF signaling is sufficient to induce a preeclampsia-like syndrome in nonpregnant women. REVIEWS IN OBSTETRICS & GYNECOLOGY 2012; 5:2-8. [PMID: 22582121 PMCID: PMC3349918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Preeclampsia (gestational proteinuric hypertension) complicates 5% to 8% of all pregnancies, and is a major cause of maternal and perinatal morbidity and mortality. It is a multisystem disorder specific to human pregnancy and the puerperium. Although the etiology is unknown, increasing evidence from both animal and human studies suggests that an imbalance in circulating pro-(vascular endothelial growth factor [VEGF], placental growth factor) and anti-angiogenic factors (soluble fms-like tyrosine kinase 1, soluble endoglin) may be important. Bevacizumab (Avastin®; Genentech, South San Francisco, CA), a humanized recombinant monoclonal IgG antibody that binds VEGF, has been shown to inhibit endothelial cell proliferation, suppress angiogenesis, and shrink a variety of solid tumors. We present two cases of bevacizumab toxicity that mimic preeclampsia with a reversible syndrome characterized by acute-onset severe hypertension, proteinuria, central nervous system irritability (headache, photophobia, blurred vision, seizures), abnormal laboratory tests (elevated liver function tests, thrombocytopenia), and evidence of reversible posterior leukoencephalopathy on neuroimaging. In both cases, the clinical and laboratory manifestations returned to normal with discontinuation of bevacizumab therapy and supportive care. Bevacizumab toxicity can mimic preeclampsia in nonpregnant women. These data suggest that interference with VEGF signaling is sufficient to induce a preeclampsia-like syndrome in nonpregnant patients. VEGF signaling therefore appears to play a central role-perhaps the central role-in the pathogenesis of preeclampsia, and provides a potential biomarker for the prediction, prevention, and treatment of this dangerous disorder.
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