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

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

doi:10.1172/JCI83918

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

Journal article

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

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, …

The Journal of clinical investigation, Vol.126(7), pp.2561-2574

07/01/2016

DOI: 10.1172/JCI83918

PMCID: PMC4922717

PMID: 27270170

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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.

Details

Title: Subtitle: Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia
Creators: Suzanne D. Burke - Beth Israel Deaconess Medical Center
Zsuzsanna K. Zsengellér
Eliyahu V. Khankin - Beth Israel Deaconess Medical Center
Agnes S. Lo - Center for Vascular Biology Research
Augustine Rajakumar - Harvard University
Jennifer J. DuPont - Tufts Medical Center
Amy McCurley - Tufts Medical Center
Mary E. Moss - Tufts Medical Center
Dongsheng Zhang - Harvard University
Christopher D. Clark - Beth Israel Deaconess Medical Center
Alice Wang - Beth Israel Deaconess Medical Center
Ellen W. Seely - Harvard University
Peter M. Kang - Beth Israel Deaconess Medical Center
Isaac E. Stillman - Beth Israel Deaconess Medical Center
Iris Z. Jaffe - Tufts Medical Center
S. Ananth Karumanchi - Beth Israel Deaconess Medical Center
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.126(7), pp.2561-2574
Publisher: American Society for Clinical Investigation
DOI: 10.1172/JCI83918
PMID: 27270170
PMCID: PMC4922717
ISSN: 0021-9738
eISSN: 1558-8238
Language: English
Date published: 07/01/2016
Academic Unit: Obstetrics and Gynecology
Record Identifier: 9984696760702771

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