Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

Maynard, Sharon E.; Min, Jiang-Yong; Merchan, Jaime; Lim, Kee-Hak; Li, Jianyi; Mondal, Susanta; Libermann, Towia A.; Morgan, James P.; Sellke, Frank W.; Stillman, Isaac E.; Epstein, Franklin H.; Sukhatme, Vikas P.; Karumanchi, S. Ananth

doi:10.1172/jci17189

Cited by 4,101Pregnancy and preeclampsia studiesNeurological Complications and SyndromesAngiogenesis and VEGF in Cancer

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

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Maynard, Sharon E., Min, Jiang-Yong, Merchan, Jaime, Lim, Kee-Hak, Li, Jianyi, Mondal, Susanta, Libermann, Towia A., Morgan, James P. +5 more·2003·Journal of Clinical Investigation

DOI 10.1172/jci17189PMC PMC151901

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Abstract

Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.

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This persistent inflammatory cascade promotes systemic insulin resistance and endothelial dysfunction, directly predisposing patients to gestational diabetes and hypertensive disorders.
“This persistent inflammatory cascade promotes systemic insulin resistance and endothelial dysfunction, directly predisposing patients to gestational diabetes and hypertensive disorders [13,15,16].”
From Trimester-Specific Bioelectrical Impedance Reference Curves in Physiological Pregnancy: Mapping Maternal Body Composition and Hydration Trajectories (2026) · cites this paper as [15]
The Introduction links excess placental sFlt1 to endothelial dysfunction and hypertension in preeclampsia, and the summary (p. 654) says it contributes to preeclamptic hypertension. These passages do not support the attributed inflammatory cascade, systemic insulin resistance, or predisposition to gestational diabetes; the mechanism described is antagonism of VEGF and PlGF. (LLM, conf=0.88)
Experimental — accuracy not yet measured
If sVEGFR-1 is administered to rats using an adenovirus vector, the animals develop hypertension, proteinuria, and glomerular endotheliosis.
“For example, if sVEGFR-1 is administered to rats using an adenovirus vector, the animals develop hypertension, proteinuria, and glomerular endotheliosis(180).”
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 [180]

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The significance of the ratio of serum soluble fms-like tyrosine kinase-1/placenta growth factor for predicting development of preeclampsia
Jiang, L. (2010) · Laboratory Medicine

Authors: Maynard, S. E., Min, J.-Y., Merchan, J., Lim, K.-H., Li, J., Mondal, S., Libermann, T. A., Morgan, J. P., Sellke, F. W., Stillman, I. E., Epstein, F. H., Sukhatme, V. P., & Karumanchi, S. A.
Affiliations: Beth Israel Deaconess Medical Center (US)
Harvard University (US)
Corresponding author: Karumanchi, S. Ananth
ORCID: Merchan, Jaime
Li, Jianyi
Mondal, Susanta
Libermann, Towia A.
Morgan, James P.
Sellke, Frank W.
Stillman, Isaac E.
Sukhatme, Vikas P.
Karumanchi, S. Ananth
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2003-03-01
Volume: 111
Issue: 5
Pages: 649-658
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci17189
PMC: PMC151901
OpenAlex: W2143180984
Cited by: 4,101
References: 51
Citations by year: 2026: 157 · 2025: 126 · 2024: 169 · 2023: 181 · 2022: 190 · 2021: 217 · 2020: 177 · 2019: 195 · 2018: 218 · 2017: 182 · 2016: 202 · 2015: 194 · 2014: 226 · 2013: 215 · 2012: 207
FWCI: 130.35
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: American Society of Nephrology
Pfizer
American Society of Clinical Oncology
Massachusetts Institute of Technology
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (U24DK058739)
Topics: Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
Health Sciences › Medicine › Psychiatry and Mental health › Neurological Complications and Syndromes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords: preeclampsia, soluble fms-like tyrosine kinase-1, endothelial dysfunction, vascular endothelial growth factor, placental growth factor, placental ischemia, hypertension, proteinuria, glomerular endotheliosis
MeSH terms: Placenta Growth Factor, Endothelium, Vascular, Enzyme-Linked Immunosorbent Assay, Female, Humans, Hypertension, Kidney, Lymphokines, Pre-Eclampsia, Pregnancy, Pregnancy Proteins, Proteinuria, Endothelial Growth Factors, Neovascularization, Physiologic, Intercellular Signaling Peptides and Proteins, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A

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Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

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