title: eNOS deficiency acts through endothelin to aggravate sFlt-1-induced pre-eclampsia-like phenotype.
abstract: Excess soluble fms-like tyrosine kinase 1 (sFlt-1) of vascular endothelial growth factor receptor 1 secreted from the placenta causes pre-eclampsia-like features by antagonizing vascular endothelial growth factor signaling, which can lead to reduced endothelial nitric oxide synthase (eNOS) activity; the effect of this concomitant decrease in eNOS activity is unknown. We tested whether the decrease in nitric oxide occurring in female mice lacking eNOS aggravates the pre-eclampsia-like phenotype induced by increased sFlt-1. Untreated eNOS-deficient female mice had higher BP than wild-type mice. Adenovirus-mediated overexpression of sFlt-1 increased systolic BP by approximately 27 mmHg and led to severe loss of fenestration of glomerular capillary endothelial cells in both eNOS-deficient and wild-type mice. However, only the eNOS-deficient sFlt-1 mice exhibited severe foot process effacement. Compared with wild-type sFlt-1 mice, eNOS-deficient sFlt-1 mice also showed markedly higher urinary albumin excretion (467±74 versus 174±23 μg/d), lower creatinine clearance (126±29 versus 452±63 μl/min), and more severe endotheliosis. Expression of preproendothelin-1 (ET-1) and its ET(A) receptor in the kidney was higher in eNOS-deficient sFlt-1 mice than in wild-type sFlt-1 mice. Furthermore, the selective ET(A) receptor antagonist ambrisentan attenuated the increases in BP and urinary albumin excretion and ameliorated endotheliosis in both wild-type and eNOS-deficient sFlt-1 mice. Ambrisentan improved creatinine clearance and podocyte effacement in eNOS-deficient sFlt-1 mice. In conclusion, reduced maternal eNOS/nitric oxide exacerbates the sFlt1-related pre-eclampsia-like phenotype through activation of the endothelin system.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: John R
authors.initials: JR
authors.lastname: Hagaman
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: J Charles
authors.initials: JC
authors.lastname: Jennette
authors.forename: James E
authors.initials: JE
authors.lastname: Faber
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.forename: Oliver
authors.initials: O
authors.lastname: Smithies
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
mesh_terms: D000419:Albuminuria / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005919:Glomerular Filtration Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency*; D010641:Phenotype; D010666:Phenylpropionates / Q000494:pharmacology; D010920:Placenta / Q000378:metabolism; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal; D011724:Pyridazines / Q000494:pharmacology; D011897:Random Allocation; D017466:Receptors, Endothelin / Q000378:metabolism; D012680:Sensitivity and Specificity; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D010666:Phenylpropionates; D011724:Pyridazines; D017466:Receptors, Endothelin; D052250:Nitric Oxide Synthase Type III; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; C467894:ambrisentan