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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 4

Augmentation of the cGMP pathway improves vascular outcomes in the sFlt1 overexpression model.

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Augmentation of the cGMP pathway improves vascular outcomes in the sFlt1...
(A) Pregnant mice given sFlt1 adenovirus at gd8 (arrow) with sildenafil citrate (sFlt1 + SILD, n = 5) maintained normal blood pressure, whereas untreated mice developed hypertension (n = 3). *P < 0.001, sFlt1 mice compared with earlier gestation days. Two-way repeated-measures ANOVA. Data for sFlt1 mice in this figure were obtained from data presented as sFlt1 group in Figure 1C. (B) Comparison of MAP and plasma sFLT1 levels between sFlt1 (n = 3) and sFlt1 + SILD mice (n = 5). ΔMAP was obtained by subtraction of individual pressure at gd17 from that at gd7. Gd7 was selected as the latest time point when all animals had no pressure differences (prior to intervention, permitting comparison). ΔMAP was significantly lower in sFlt1 + SILD–treated mice (*P < 0.01), while plasma sFLT1 levels at gd17 were similar. Data for sFlt1 mice in this figure were obtained from data presented as sFlt1 group in Figure 1D. (C) Ex vivo contraction of mesenteric vessels in response to Ang II was restored by treatment with oral sildenafil in comparison with sFlt1 mice at gd17 (n = 8 per group). *P < 0.05. (D) Representative images of aorta isolated from sFlt1 (left) and sFlt1 + SILD (right) mice at gd17 staining for MitoSOX Red (top; scale bar: 50 μm) and nitrotyrosine (bottom; scale bar: 20 μm). (E) Quantitation of MitoSOX Red immunofluorescence in aortic tissue from gd17 sFlt1- and sFlt1 + SILD–treated mice. OD per area (pixels2) of tissue was calculated in 5 high-power fields per sample (n = 3 aortas per group). *P < 0.001 versus sFlt1 by 2-way ANOVA and Tukey’s post hoc test. Data for sFlt1 mice in this figure were obtained from summary sFlt1 data presented in Supplemental Figure 3B. (F) Sildenafil treatment increased urinary cGMP compared with sFlt1 alone. (n = 7 per group.) *P < 0.01. Data represent the mean ± SEM, analyzed by unpaired 2-tailed t test with Welch’s correction (except where noted).

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

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