Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia.
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.
Suzanne D
SD
Burke
Zsuzsanna K
ZK
Zsengellér
Eliyahu V
EV
Khankin
Agnes S
AS
Lo
Augustine
A
Rajakumar
Jennifer J
JJ
DuPont
Amy
A
McCurley
Mary E
ME
Moss
Dongsheng
D
Zhang
Christopher D
CD
Clark
Alice
A
Wang
Ellen W
EW
Seely
Peter M
PM
Kang
Isaac E
IE
Stillman
Iris Z
IZ
Jaffe
S Ananth
SA
Karumanchi
D000804:Angiotensin II / Q000378:metabolism*; D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000737:chemistry; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal; D015398:Signal Transduction; D000068677:Sildenafil Citrate / Q000627:therapeutic use; D016896:Treatment Outcome; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
D000809:Angiotensins; D000804:Angiotensin II; D000068677:Sildenafil Citrate; D052250:Nitric Oxide Synthase Type III; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D019331:NG-Nitroarginine Methyl Ester