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

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

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 3

sFLT1 alters the vascular endothelium by decreasing eNOS function.

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sFLT1 alters the vascular endothelium by decreasing eNOS function. (A) V...
(A) VEGF induces dose-dependent activation of eNOS in HUVECs, as measured by eNOS phosphorylation at Ser1177 (phospho-eNOS) relative to total eNOS by Western blotting. This is inhibited by excess sFLT1 (1 μg/ml). Representative of 4 individual experiments. (B) Densitometry of phospho-eNOS/total eNOS bands plotted as a percentage of control. VEGF-induced eNOS phosphorylation in HUVECs was approximately 2.5-fold above control at 10 ng/ml of VEGF (P < 0.001 vs. all other groups). The increase in VEGF-induced phosphorylation was blocked when cells were preincubated with excess of sFLT1; *P < 0.001. Analysis by 2-way repeated-measures ANOVA, n = 4 individual experiments. (C) IHC for phospho-eNOS expression in mesenteric resistance vessels from gd17 pregnant mice given CMV-null (left) or sFlt1 (right). Images are representative of 4–5 mice per group. Scale bar: 100 μm. (D) Administration of l-NAME in drinking water during pregnancy phenocopies sFlt1-induced Ang II hypersensitivity. Pregnant mice were given 1 g/l l-NAME in drinking water at gd8 and then implanted with s.c. osmotic minipumps infusing Ang II or saline control at gd12. Blood pressure became significantly elevated only in mice given l-NAME and Ang II (n = 4 per group; daily mean ± SEM). Two-way repeated-measures ANOVA, *P < 0.01. (E) Comparison of MAP and plasma sFLT1 between l-NAME + saline and l-NAME + Ang II pregnant mice (n = 4 per group). 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). *P < 0.01. Analysis by 1-way ANOVA with Bonferroni’s post-hoc test. (F) Representative images of aorta isolated from CMV-null (left), sFlt1 (middle), and l-NAME (right) mice at gd17 staining for MitoSOX Red (top; scale bar: 50 μm) and nitrotyrosine (bottom; scale bar: 20 μm). All data represent the mean ± SEM.