Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction
Abstract
Background Preeclampsia is associated with placental ischemia/hypoxia and secretion of soluble fms-like tyrosine kinase 1 and soluble endoglin into the maternal circulation. This causes widespread endothelial dysfunction that manifests clinically as hypertension and multisystem organ injury. Recently, small molecule inhibitors of hypoxic inducible factor 1α have been found to reduce soluble fms-like tyrosine kinase 1 and soluble endoglin secretion. However, their safety profile in pregnancy is unknown. Metformin is safe in pregnancy and is also reported to inhibit hypoxic inducible factor 1α by reducing mitochondrial electron transport chain activity.Objective The purposes of this study were to determine (1) the effects of metformin on placental soluble fms-like tyrosine kinase 1 and soluble endoglin secretion, (2) to investigate whether the effects of metformin on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion are regulated through the mitochondrial electron transport chain, and (3) to examine its effects on endothelial dysfunction, maternal blood vessel vasodilation, and angiogenesis.Study design We performed functional (in vitro and ex vivo) experiments using primary human tissues to examine the effects of metformin on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion from placenta, endothelial cells, and placental villous explants. We used succinate, mitochondrial complex II substrate, to examine whether the effects of metformin on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion were mediated through the mitochondria. We also isolated mitochondria from preterm preeclamptic placentas and gestationally matched control subjects and measured mitochondrial electron transport chain activity using kinetic spectrophotometric assays. Endothelial cells or whole maternal vessels were incubated with metformin to determine whether it rescued endothelial dysfunction induced by either tumor necrosis factor-α (to endothelial cells) or placenta villous explant-conditioned media (to whole vessels). Finally, we examined the effects of metformin on angiogenesis on maternal omental vessel explants.Results Metformin reduced soluble fms-like tyrosine kinase 1 and soluble endoglin secretion from primary endothelial cells, villous cytotrophoblast cells, and preterm preeclamptic placental villous explants. The reduction in soluble fms-like tyrosine kinase 1 and soluble endoglin secretion was rescued by coadministration of succinate, which suggests that the effects of metformin on soluble fms-like tyrosine kinase 1 and soluble endoglin were likely to be regulated at the level of the mitochondria. In addition, the mitochondrial electron transport chain inhibitors rotenone and antimycin reduced soluble fms-like tyrosine kinase 1 secretion, which further suggests that soluble fms-like tyrosine kinase 1 secretion is regulated through the mitochondria. Mitochondrial electron transport chain activity in preterm preeclamptic placentas was increased compared with gestation-matched control subjects. Metformin improved features of endothelial dysfunction relevant to preeclampsia. It reduced endothelial cell messenger RNA expression of vascular cell adhesion molecule 1 that was induced by tumor necrosis factor-α (vascular cell adhesion molecule 1 is an inflammatory adhesion molecule up-regulated with endothelial dysfunction and is increased in preeclampsia). Placental conditioned media impaired bradykinin-induced vasodilation; this effect was reversed by metformin. Metformin also improved whole blood vessel angiogenesis impaired by fms-like tyrosine kinase 1.Conclusion Metformin reduced soluble fms-like tyrosine kinase 1 and soluble endoglin secretion from primary human tissues, possibly by inhibiting the mitochondrial electron transport chain. The activity of the mitochondrial electron transport chain was increased in preterm preeclamptic placenta. Metformin reduced endothelial dysfunction, enhanced vasodilation in omental arteries, and induced angiogenesis. Metformin has potential to prevent or treat preeclampsia.
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Preeclampsia has the potential to be added to the list of conditions that metformin may treat.
“The good news for obstetricians is that preeclampsia has the potential to be added to this list (20).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [20]
Overall, Brownfoot et al.'s findings suggest that metformin may have a role in the prevention of preeclampsia through its effect on cell metabolism, on the anti-angiogenic state, and on other processes associated with this obstetrical syndrome.
“Overall, Brownfoot et al.’s findings suggest that metformin may have a role in the prevention of preeclampsia through its effect on cell metabolism, on the anti-angiogenic state, and, most likely, on other processes associated with this obstetrical syndrome(20).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [20]
Brownfoot et al. reported that metformin reduced the production of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sENG) in a dose-dependent manner by endothelial cells, villous trophoblast, and villous explants.
“Brownfoot et al.(20) from the Translational Obstetrics Group of the Department of Obstetrics and Gynecology, Mercy Hospital for Women, at the University of Melbourne, Heidelberg, Victoria, Australia, reported that metformin reduced the production of soluble fms-like tyrosine kinase-1 (sFlt-1, also known as soluble vascular endothelial growth factor receptor 1 or sVEGFR-1) and soluble endoglin (sEN”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [20]
Metformin reverses the impairment of vascular relaxation induced by incubating the maternal blood vessels obtained from the omentum at the time of cesarean delivery with placental conditioned media of patients with preeclampsia.
“However, the most persuasive evidence that metformin has a vascular effect is the finding that it reverses the impairment of vascular relaxation induced by incubating the maternal blood vessels obtained from the omentum at the time of cesarean delivery with placental conditioned media of patients with preeclampsia(20).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [20]
Metformin abrogated the reduction of angiogenic sprouting induced in human omental vessel explants by incubation with VEGFR-1.
“Metformin also abrogated the reduction of angiogenic sprouting induced in human omental vessel explants by incubation with VEGFR-1 (Figure 7)(20).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [20]
Brownfoot et al. suggested that metformin regulates these anti-angiogenic factors at the level of the mitochondria.
“the report also suggested that metformin regulates these anti-angiogenic factors at the level of the mitochondria.”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [20]
The reduction in the secretion of anti-angiogenic factors by metformin was reversed when succinate (whose metabolism via complex II bypasses complex I) was used as an electron source.
“The reduction in the secretion of anti-angiogenic factors by metformin was reversed when succinate (whose metabolism via complex II bypasses complex I) was used as an electron source(20).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [20]
Brownfoot et al. demonstrated that other electron transport chain inhibitors (antimycin and rotenone) blocked secretion of sFlt-1 and soluble endoglin, suggesting that the electron transport chain is the major effector of the benefits of metformin.
“However, Brownfoot et al.(20) demonstrated that other electron transport chain inhibitors (antimycin and rotenone) blocked secretion of sFlt-1 and soluble endoglin, suggesting that the electron transport chain is the major effector of the benefits of metformin.”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [20]
Succinate in the absence of metformin appears to have no effect.
“Indeed, succinate in the absence of metformin appears to have no effect(20).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [20]
Brownfoot et al. found that metformin can improve endothelial dysfunction, reduce the expression of vascular adhesion molecule 1 mRNA induced by TNFα, and improve whole-blood vessel angiogenesis impaired by sFlt-1 or sVEGFR-1.
“Brownfoot et al.(20) found that metformin can improve endothelial dysfunction, reduce the expression of vascular adhesion molecule 1 mRNA induced by TNFα, and improve whole-blood vessel angiogenesis impaired by sFlt-1 or sVEGFR-1.”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [20]
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Cohen, J. M., Kramer, M. S., Platt, R. W., Basso, O., Evans, R. W., & Kahn, S. R. (2015) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2015.07.027 · Cited by 57 · see citing works
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Angiogenic markers in pregnancies conceived through in vitro fertilization
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Expectant management of mild preeclampsia versus superimposed preeclampsia up to 37 weeks
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Prognosis after maternal placental events and revascularization: PAMPER study
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Metformin, B12, and Enhanced Breast Cancer Response to Chemotherapy
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Preeclampsia: 2 placental phenotypes, 1 etiology?
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A global view of hypertensive disorders and diabetes mellitus during pregnancy
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The emerging role of metformin in gestational diabetes mellitus
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- Authors
- Brownfoot, F. C., Hastie, R., Hannan, N. J., Cannon, P., Tuohey, L., Parry, L. J., Senadheera, S., Illanes, S. E., Kaitu’u-Lino, T. J., & Tong, S.
- Affiliations
- The University of Melbourne (AU)
- Universidad de Los Andes, Chile (CL)
- Corresponding author
- Tong, Stephen
- ORCID
- Venue
- American Journal of Obstetrics and Gynecology
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 214
- Issue
- 3
- Pages
- 356.e1-356.e15
- ISSN
- 0002-9378 (ISSN-L)
- OpenAlex
- W2210100288
- Cited by
- 222
- References
- 90
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 19 · 2023: 15 · 2022: 18 · 2021: 25 · 2020: 28 · 2019: 28 · 2018: 25 · 2017: 22 · 2016: 11
- FWCI
- 22.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Obstetrics and Gynecology (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Health Sciences › Medicine › Psychiatry and Mental health › Neurological Complications and Syndromes
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- metformin, preeclampsia, soluble fms-like tyrosine kinase-1, soluble endoglin, endothelial dysfunction, mitochondrial electron transport chain, angiogenesis, TNF-α, placental villi, maternal hypertension, pregnancy safety, succinic acid
- MeSH terms
- Endoglin, Cardiovascular Agents, Endothelium, Vascular, Female, Humans, Metformin, Placenta, Pre-Eclampsia, Pregnancy, Receptors, Cell Surface, Vasodilation, Biomarkers, Antigens, CD, Treatment Outcome, Vascular Endothelial Growth Factor Receptor-1, Electron Transport Chain Complex Proteins, In Vitro Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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