title: Uterine artery dysfunction in pregnant ACE2 knockout mice is associated with placental hypoxia and reduced umbilical blood flow velocity.
abstract: Angiotensin-converting enzyme 2 (ACE2) knockout is associated with reduced fetal weight at late gestation; however, whether uteroplacental vascular and/or hemodynamic disturbances underlie this growth-restricted phenotype is unknown. Uterine artery reactivity and flow velocities, umbilical flow velocities, trophoblast invasion, and placental hypoxia were determined in ACE2 knockout (KO) and C57Bl/6 wild-type (WT) mice at day 14 of gestation. Although systolic blood pressure was higher in pregnant ACE2 KO vs. WT mice (102.3 ± 5.1 vs. 85.1 ± 1.9 mmHg, n = 5-6), the magnitude of difference was similar to that observed in nonpregnant ACE2 KO vs. WT mice. Maternal urinary protein excretion, serum creatinine, and kidney or heart weights were not different in ACE2 KO vs. WT. Fetal weight and pup-to-placental weight ratio were lower in ACE2 KO vs. WT mice. A higher sensitivity to Ang II [pD2 8.64 ± 0.04 vs. 8.5 ± 0.03 (-log EC50)] and greater maximal contraction to phenylephrine (169.0 ± 9.0 vs. 139.0 ± 7.0% KMAX), were associated with lower immunostaining for Ang II receptor 2 and fibrinoid content of the uterine artery in ACE2 KO mice. Uterine artery flow velocities and trophoblast invasion were similar between study groups. In contrast, umbilical artery peak systolic velocities (60.2 ± 4.5 vs. 75.1 ± 4.5 mm/s) and the resistance index measured using VEVO 2100 ultrasound were lower in the ACE2 KO vs. WT mice. Immunostaining for pimonidazole, a marker of hypoxia, and hypoxia-inducible factor-2α were higher in the trophospongium and placental labyrinth of the ACE2 KO vs. WT. In summary, placental hypoxia and uterine artery dysfunction develop before major growth of the fetus occurs and may explain the fetal growth restricted phenotype.
authors.affiliation: The Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina; lyamaley@wakehealth.edu.
authors.forename: Liliya M
authors.initials: LM
authors.lastname: Yamaleyeva
authors.affiliation: The Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina; Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina;
authors.forename: Victor M
authors.initials: VM
authors.lastname: Pulgar
authors.affiliation: Department of Pharmacology, Tulane University, New Orleans, Louisiana; and.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Lindsey
authors.affiliation: The Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina;
authors.forename: Larissa
authors.initials: L
authors.lastname: Yamane
authors.affiliation: The Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina;
authors.forename: Jasmina
authors.initials: J
authors.lastname: Varagic
authors.affiliation: The Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina;
authors.forename: Carolynne
authors.initials: C
authors.lastname: McGee
authors.affiliation: The Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina;
authors.forename: Mauro
authors.initials: M
authors.lastname: daSilva
authors.affiliation: The Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina;
authors.forename: Paula
authors.initials: P
authors.lastname: Lopes Bonfa
authors.affiliation: Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, North Carolina.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Gurley
authors.affiliation: The Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina;
authors.forename: K Bridget
authors.initials: KB
authors.lastname: Brosnihan
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001783:Blood Flow Velocity; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D010920:Placenta / Q000098:blood supply / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D021041:Placental Circulation / Q000502:physiology; D011247:Pregnancy; D014470:Umbilical Cord / Q000098:blood supply* / Q000503:physiopathology; D055988:Uterine Artery / Q000503:physiopathology*
chemical_list: D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: angiotensin II; fetal growth restriction; hypoxia; vascular reactivity; vasoconstriction