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 1

Ang II resistance characterizes normal pregnancy, while sFlt1 overexpression is sufficient to cause Ang II sensitivity.

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Ang II resistance characterizes normal pregnancy, while sFlt1 overexpres...
(A) Blood pressure measurements in nonpregnant (n = 5) and pregnant CD-1 mice (n = 3) with Ang II infusion via s.c. osmotic minipump beginning on day 12. *P < 0.05 for mean arterial pressure (MAP) in pregnant mice versus nonpregnant mice. (B) MAP comparison between nonpregnant (n = 5) and pregnant mice (n = 3) infused with Ang II. ΔMAP was obtained by subtraction of individual pressure at day 17 from that at day 7. Day 7 was selected as the latest time point when all animals had no pressure differences (prior to intervention). *P < 0.001 by unpaired 2-tailed t test. (C) MAP of CMV-null (n = 5) and sFlt1-injected (n = 3) mice over gestation. Mice were injected at gd8 (arrow). MAP in sFlt1 mice was significantly increased relative to CMV-null and within-group baseline beginning at gd12; *P < 0.001. (D) Comparison of MAP between CMV-null mice (n = 5) and sFlt1 mice (n = 3). ΔMAP was obtained by subtraction of individual pressure at gd17 from that at gd7. *P < 0.01 by 1-way ANOVA and Bonferroni’s post-hoc test. (E) ΔMAP following acute i.v. Ang II bolus (30 ng in 30 μl saline plotted as medians (minimum and maximum), n = 3–5. ΔMAP was calculated by subtraction of individual data points from preinjection data (t = 0) for each animal every 5 minutes for 15 minutes following injection. Data were recorded as nonpregnant (NP), at increasing gestational days, and postpartum (PP). *P = 0.01 compared with NP and sFlt1 at gd14. (F) MAP of CMV-null (n = 3) and sFlt1-injected (n = 4) mice given chronic Ang II over gestation. Mice were injected with adenovirus at gd8 (arrow) and implanted with s.c. osmotic minipumps containing Ang II at gd12 (dashed line). *P < 0.01 for MAP in sFlt1 mice versus CMV-null mice. Data for CMV-null mice in this figure were obtained from data shown as the pregnant group in A. (G) Comparison of MAP between CMV-null (n = 3) and sFlt1 mice (n = 4) given chronic Ang II. ΔMAP was obtained by subtraction of individual pressure at gd17 from that at gd7. *P < 0.05 by 1-way ANOVA with Bonferroni’s post-hoc test. Data for the CMV-null mice in this figure were obtained from data shown as the pregnant group in B. (H) Contraction of ex vivo mesenteric resistance vessels in gd17 CMV-null or sFlt1 mice in response to Ang II or phenylephrine (n = 4 per group). *P < 0.05 by unpaired 2-tailed t test. Analyses used 2-way ANOVA with repeated measures, with the exception of B, D, G, and H, as indicated. All data represent the mean ± SEM, except in E.