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Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia
Suzanne D. Burke, … , Iris Z. Jaffe, S. Ananth Karumanchi
Suzanne D. Burke, … , Iris Z. Jaffe, S. Ananth Karumanchi
Published June 6, 2016
Citation Information: J Clin Invest. 2016;126(7):2561-2574. https://doi.org/10.1172/JCI83918.
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Concise Communication Reproductive biology Article has an altmetric score of 10

Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia

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Abstract

Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes.

Authors

Suzanne D. Burke, Zsuzsanna K. Zsengellér, Eliyahu V. Khankin, Agnes S. Lo, Augustine Rajakumar, Jennifer J. DuPont, Amy McCurley, Mary E. Moss, Dongsheng Zhang, Christopher D. Clark, Alice Wang, Ellen W. Seely, Peter M. Kang, Isaac E. Stillman, Iris Z. Jaffe, S. Ananth Karumanchi

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Figure 2

Assessment of the renin-angiotensin system in mice overexpressing sFlt1.

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Assessment of the renin-angiotensin system in mice overexpressing sFlt1....
(A and B) ELISA of plasma renin (A) and Ang II (B) from gd17 CMV-null (n = 14) and sFlt1 (n = 9) pregnant mice. Unpaired 2-tailed t test; *P < 0.05. (C and D) Gene expression analysis of renal tissue (C) and mesenteric vessels (D) obtained from CMV-null and sFlt1 mice as nonpregnant (NP), gd14, gd17, and postpartum (PP). mRNA analysis (quantitative RT-PCR) was completed for the Ang II receptors (at1ra, at1rb, and at2r). All data were normalized to β-actin (ΔCt). Comparisons between groups of NP, gd14, gd17, and postpartum (PP) mice revealed no differences. Nonpregnant mice were injected with adenovirus at least 7 days before collection. n = 3–8 mice per time point were assayed per tissue. All data represent the mean ± SEM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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