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Original Article

Endothelial NO Synthase Augments Fetoplacental Blood Flow, Placental Vascularization, and Fetal Growth in Mice

Shathiyah Kulandavelu, Kathie J. Whiteley, Shannon A. Bainbridge, Dawei Qu, S. Lee Adamson
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https://doi.org/10.1161/HYPERTENSIONAHA.112.201996
Hypertension. 2012;HYPERTENSIONAHA.112.201996
Originally published November 12, 2012
Shathiyah Kulandavelu
From the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (S.K., K.J.W., S.A.B., D.Q., S.L.A.); and the Departments of Physiology, and Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada (S.K., S.A.B., S.L.A.).
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Kathie J. Whiteley
From the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (S.K., K.J.W., S.A.B., D.Q., S.L.A.); and the Departments of Physiology, and Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada (S.K., S.A.B., S.L.A.).
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Shannon A. Bainbridge
From the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (S.K., K.J.W., S.A.B., D.Q., S.L.A.); and the Departments of Physiology, and Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada (S.K., S.A.B., S.L.A.).
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Dawei Qu
From the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (S.K., K.J.W., S.A.B., D.Q., S.L.A.); and the Departments of Physiology, and Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada (S.K., S.A.B., S.L.A.).
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S. Lee Adamson
From the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (S.K., K.J.W., S.A.B., D.Q., S.L.A.); and the Departments of Physiology, and Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada (S.K., S.A.B., S.L.A.).
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Abstract

It is not known whether eNOS deficiency in the mother or the conceptus (ie, placenta and fetus) causes fetal growth restriction in mice lacking the endothelial NO synthase gene (eNOS knockout [KO]). We hypothesized that eNOS sustains fetal growth by maintaining low fetoplacental vascular tone and promoting fetoplacental vascularity and that this is a conceptus effect and is independent of maternal genotype. We found that eNOS deficiency blunted fetal growth, and blunted the normal increase in umbilical blood flow and umbilical venous diameter and the decrease in umbilical arterial Resistance Index in late gestation (14.5–17.5 days) in eNOS KO relative to C57Bl/6J controls. On day 17.5, fetoplacental capillary lobule length and capillary density in vascular corrosion casts were reduced in eNOS KO placentas. Reduced vascularization may be a result of decreased vascular endothelial growth factor mRNA and protein expression in eNOS KO placentas at this stage. These factors, combined with significant anemia found in eNOS KO fetuses, would be anticipated to reduce fetal oxygen delivery and contribute to the fetal tissue hypoxia that was detected in the heart, lung, kidney, and liver by immunohistochemistry using pimonidazole. Although maternal eNOS deficiency impairs uteroplacental adaptations to pregnancy, maternal genotype was not a significant factor affecting growth in heterozygous conceptuses. This indicates that fetal growth restriction was primarily caused by conceptus eNOS deficiency. In mice, placental hemodynamic and vascular changes with gestation and growth restriction showed strong parallels with human pregnancy. Thus, the eNOS KO model could provide insights into the pathogenesis of human intrauterine growth restriction.

  • angiogenesis
  • pregnancy
  • intrauterine growth restriction
  • vascular growth factor
  • hypoxia
  • genetics-knockout models
  • NO
  • Received July 17, 2012.
  • Revision received August 2, 2011.
  • Accepted October 11, 2012.
  • © 2012 American Heart Association, Inc.
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    Endothelial NO Synthase Augments Fetoplacental Blood Flow, Placental Vascularization, and Fetal Growth in Mice
    Shathiyah Kulandavelu, Kathie J. Whiteley, Shannon A. Bainbridge, Dawei Qu and S. Lee Adamson
    Hypertension. 2012;HYPERTENSIONAHA.112.201996, originally published November 12, 2012
    https://doi.org/10.1161/HYPERTENSIONAHA.112.201996

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    Endothelial NO Synthase Augments Fetoplacental Blood Flow, Placental Vascularization, and Fetal Growth in Mice
    Shathiyah Kulandavelu, Kathie J. Whiteley, Shannon A. Bainbridge, Dawei Qu and S. Lee Adamson
    Hypertension. 2012;HYPERTENSIONAHA.112.201996, originally published November 12, 2012
    https://doi.org/10.1161/HYPERTENSIONAHA.112.201996
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