Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis
Abstract Background Pre-eclampsia (PE) is one of the leading causes of maternal and fetal morbidity/mortality during pregnancy, and alpha-2-macroglobulin (A2M) is associated with inflammatory signaling; however, the pathophysiological mechanism by which A2M is involved in PE development is not yet u...
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| Format: | Article |
| Language: | English |
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BMC
2023-03-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-023-02807-9 |
| _version_ | 1797864532142456832 |
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| author | Jingyun Wang Ping Zhang Mengyuan Liu Zhengrui Huang Xiaofeng Yang Yuzhen Ding Jia Liu Xin Cheng Shujie Xu Meiyao He Fengxiang Zhang Guang Wang Ruiman Li Xuesong Yang |
| author_facet | Jingyun Wang Ping Zhang Mengyuan Liu Zhengrui Huang Xiaofeng Yang Yuzhen Ding Jia Liu Xin Cheng Shujie Xu Meiyao He Fengxiang Zhang Guang Wang Ruiman Li Xuesong Yang |
| author_sort | Jingyun Wang |
| collection | DOAJ |
| description | Abstract Background Pre-eclampsia (PE) is one of the leading causes of maternal and fetal morbidity/mortality during pregnancy, and alpha-2-macroglobulin (A2M) is associated with inflammatory signaling; however, the pathophysiological mechanism by which A2M is involved in PE development is not yet understood. Methods Human placenta samples, serum, and corresponding clinical data of the participants were collected to study the pathophysiologic mechanism underlying PE. Pregnant Sprague–Dawley rats were intravenously injected with an adenovirus vector carrying A2M via the tail vein on gestational day (GD) 8.5. Human umbilical artery smooth muscle cells (HUASMCs), human umbilical vein endothelial cells (HUVECs), and HTR-8/SVneo cells were transfected with A2M-expressing adenovirus vectors. Results In this study, we demonstrated that A2M levels were significantly increased in PE patient serum, uterine spiral arteries, and feto-placental vasculature. The A2M-overexpression rat model closely mimicked the characteristics of PE (i.e., hypertension in mid-to-late gestation, histological and ultrastructural signs of renal damage, proteinuria, and fetal growth restriction). Compared to the normal group, A2M overexpression significantly enhanced uterine artery vascular resistance and impaired uterine spiral artery remodeling in both pregnant women with early-onset PE and in pregnant rats. We found that A2M overexpression was positively associated with HUASMC proliferation and negatively correlated with cell apoptosis. In addition, the results demonstrated that transforming growth factor beta 1 (TGFβ1) signaling regulated the effects of A2M on vascular muscle cell proliferation described above. Meanwhile, A2M overexpression regressed rat placental vascularization and reduced the expression of angiogenesis-related genes. In addition, A2M overexpression reduced HUVEC migration, filopodia number/length, and tube formation. Furthermore, HIF-1α expression was positively related to A2M, and the secretion of sFLT-1 and PIGF of placental origin was closely related to PE during pregnancy or A2M overexpression in rats. Conclusions Our data showed that gestational A2M overexpression can be considered a contributing factor leading to PE, causing detective uterine spiral artery remodeling and aberrant placental vascularization. |
| first_indexed | 2024-04-09T22:53:25Z |
| format | Article |
| id | doaj.art-f57236d42d4a456697810aa3aa1bcf2d |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-09T22:53:25Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-f57236d42d4a456697810aa3aa1bcf2d2023-03-22T11:33:00ZengBMCBMC Medicine1741-70152023-03-0121112210.1186/s12916-023-02807-9Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesisJingyun Wang0Ping Zhang1Mengyuan Liu2Zhengrui Huang3Xiaofeng Yang4Yuzhen Ding5Jia Liu6Xin Cheng7Shujie Xu8Meiyao He9Fengxiang Zhang10Guang Wang11Ruiman Li12Xuesong Yang13Department of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan UniversityDepartment of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan UniversityDepartment of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan UniversityDepartment of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan UniversityDepartment of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan UniversityDepartment of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan UniversityDepartment of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan UniversityInternational Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan UniversityInternational Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan UniversityInternational Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan UniversityDepartment of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan UniversityInternational Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan UniversityDepartment of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan UniversityInternational Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan UniversityAbstract Background Pre-eclampsia (PE) is one of the leading causes of maternal and fetal morbidity/mortality during pregnancy, and alpha-2-macroglobulin (A2M) is associated with inflammatory signaling; however, the pathophysiological mechanism by which A2M is involved in PE development is not yet understood. Methods Human placenta samples, serum, and corresponding clinical data of the participants were collected to study the pathophysiologic mechanism underlying PE. Pregnant Sprague–Dawley rats were intravenously injected with an adenovirus vector carrying A2M via the tail vein on gestational day (GD) 8.5. Human umbilical artery smooth muscle cells (HUASMCs), human umbilical vein endothelial cells (HUVECs), and HTR-8/SVneo cells were transfected with A2M-expressing adenovirus vectors. Results In this study, we demonstrated that A2M levels were significantly increased in PE patient serum, uterine spiral arteries, and feto-placental vasculature. The A2M-overexpression rat model closely mimicked the characteristics of PE (i.e., hypertension in mid-to-late gestation, histological and ultrastructural signs of renal damage, proteinuria, and fetal growth restriction). Compared to the normal group, A2M overexpression significantly enhanced uterine artery vascular resistance and impaired uterine spiral artery remodeling in both pregnant women with early-onset PE and in pregnant rats. We found that A2M overexpression was positively associated with HUASMC proliferation and negatively correlated with cell apoptosis. In addition, the results demonstrated that transforming growth factor beta 1 (TGFβ1) signaling regulated the effects of A2M on vascular muscle cell proliferation described above. Meanwhile, A2M overexpression regressed rat placental vascularization and reduced the expression of angiogenesis-related genes. In addition, A2M overexpression reduced HUVEC migration, filopodia number/length, and tube formation. Furthermore, HIF-1α expression was positively related to A2M, and the secretion of sFLT-1 and PIGF of placental origin was closely related to PE during pregnancy or A2M overexpression in rats. Conclusions Our data showed that gestational A2M overexpression can be considered a contributing factor leading to PE, causing detective uterine spiral artery remodeling and aberrant placental vascularization.https://doi.org/10.1186/s12916-023-02807-9A2MPETGFβ1Uterine spiral artery remodelingPlacental vascularization |
| spellingShingle | Jingyun Wang Ping Zhang Mengyuan Liu Zhengrui Huang Xiaofeng Yang Yuzhen Ding Jia Liu Xin Cheng Shujie Xu Meiyao He Fengxiang Zhang Guang Wang Ruiman Li Xuesong Yang Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis BMC Medicine A2M PE TGFβ1 Uterine spiral artery remodeling Placental vascularization |
| title | Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis |
| title_full | Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis |
| title_fullStr | Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis |
| title_full_unstemmed | Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis |
| title_short | Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis |
| title_sort | alpha 2 macroglobulin is involved in the occurrence of early onset pre eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis |
| topic | A2M PE TGFβ1 Uterine spiral artery remodeling Placental vascularization |
| url | https://doi.org/10.1186/s12916-023-02807-9 |
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