title: Site-specific increases in utero- and fetoplacental arterial vascular resistance in eNOS-deficient mice due to impaired arterial enlargement.
abstract: The sites of elevated vascular resistance that impede placental perfusion in pathological pregnancies are unknown. In the current study, we identified these sites in a knockout mouse model (eNOS(-/-)) with reduced uterine (-55%) and umbilical (-29%) artery blood flows caused by endothelial nitric oxide synthase deficiency. Uteroplacental and fetoplacental arterial vascular trees of pregnant mice near term were imaged using x-ray microcomputed tomography (n = 5-10 placentas from 3-5 dams/group). The resulting three-dimensional images were analyzed to assess vessel geometry and vascular resistance. In control and eNOS(-/-) trees, ∼90% of total uteroplacental vascular resistance was located in the radial arteries. Changes in eNOS(-/-) vessel geometry, including 30% reductions in uterine, radial, and spiral artery diameters, were calculated to increase arterial resistance downstream of the uterine artery by 2.3-fold, predicting a 57% decrease in uterine blood flow. Despite large reductions in eNOS(-/-) spiral arteries (-55% by volume) and maternal canals (-67% by volume), these vessels were relatively minor contributors to resistance. In the eNOS(-/-) fetoplacental tree, the number of arterioles (50-75 μm diameter) increased by 26%. Nevertheless, calculated resistance rose by 19%, predominantly because arteries near the periphery of the tree selectively exhibited a 7%-9% diameter reduction. We conclude that previously observed decreases in uterine and umbilical blood flows in eNOS(-/-) pregnancies are associated with markedly divergent structural changes in the uteroplacental versus fetoplacental circulations. Results showed the radial arteries were critical determinants of uteroplacental resistance in mice and therefore warrant greater attention in future studies in pathological human pregnancies.
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Monique Y
authors.initials: MY
authors.lastname: Rennie
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anum
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Kathie J
authors.initials: KJ
authors.lastname: Whiteley
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada jgsled@mouseimaging.ca.
authors.forename: John G
authors.initials: JG
authors.lastname: Sled
authors.affiliation: Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: S Lee
authors.initials: SL
authors.lastname: Adamson
mesh_terms: D000818:Animals; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D010920:Placenta / Q000098:blood supply* / Q000378:metabolism; D021041:Placental Circulation / Q000235:genetics*; D011247:Pregnancy; D017534:Radial Artery / Q000000981:diagnostic imaging* / Q000378:metabolism; D011859:Radiography; D055988:Uterine Artery / Q000000981:diagnostic imaging* / Q000378:metabolism; D014599:Uterus / Q000098:blood supply / Q000378:metabolism; D014655:Vascular Resistance / Q000235:genetics*
chemical_list: D052250:Nitric Oxide Synthase Type III
keywords: endothelial NO synthase; fetoplacental circulation; hemodynamics; microcomputed tomography; placenta; uteroplacental circulation