Effects of Maternal Sildenafil Treatment on Vascular Function in Growth-Restricted Fetal Sheep

Ishmael M. Inocencio, Graeme R. Polglase, Suzanne L. Miller, Arvind Sehgal, Amy E. Sutherland, Jamie Mihelakis, Anqi Li, Beth J. Allison

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objective- The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Approach and Results- Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. Conclusions- SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.

Original languageEnglish
Pages (from-to)731-740
Number of pages10
JournalArteriosclerosis, Thrombosis and Vascular Biology
Volume39
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

Keywords

  • fetus
  • myography
  • placenta
  • sheep
  • sildenafil citrate

Cite this

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title = "Effects of Maternal Sildenafil Treatment on Vascular Function in Growth-Restricted Fetal Sheep",
abstract = "Objective- The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Approach and Results- Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. Conclusions- SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.",
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Effects of Maternal Sildenafil Treatment on Vascular Function in Growth-Restricted Fetal Sheep. / Inocencio, Ishmael M.; Polglase, Graeme R.; Miller, Suzanne L.; Sehgal, Arvind; Sutherland, Amy E.; Mihelakis, Jamie; Li, Anqi; Allison, Beth J.

In: Arteriosclerosis, Thrombosis and Vascular Biology, Vol. 39, No. 4, 01.04.2019, p. 731-740.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Effects of Maternal Sildenafil Treatment on Vascular Function in Growth-Restricted Fetal Sheep

AU - Inocencio, Ishmael M.

AU - Polglase, Graeme R.

AU - Miller, Suzanne L.

AU - Sehgal, Arvind

AU - Sutherland, Amy E.

AU - Mihelakis, Jamie

AU - Li, Anqi

AU - Allison, Beth J.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Objective- The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Approach and Results- Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. Conclusions- SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.

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KW - fetus

KW - myography

KW - placenta

KW - sheep

KW - sildenafil citrate

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U2 - 10.1161/ATVBAHA.119.312366

DO - 10.1161/ATVBAHA.119.312366

M3 - Article

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JO - Arteriosclerosis, Thrombosis and Vascular Biology

JF - Arteriosclerosis, Thrombosis and Vascular Biology

SN - 1079-5642

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