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.

Maternal sildenafil impairs the cardiovascular adaptations to chronic hypoxaemia in fetal sheep

“…2009; Inocencio et al . 2019). It is reasonable to assume the increased fetal hypoxaemia observed in our current study may have also been driven by similar alterations in maternal and/or placental blood flow by SC.…”

“…2018; Inocencio et al . 2019) and PDE5 receptors are found in the developing fetus (Luong et al . 2011).…”

“…2016; Inocencio et al . 2019), and therefore antenatal SC treatment may have direct effects on fetal blood vessels (Francis & Corbin, 2005). We propose that it is important to consider the haemodynamic effects of SC in the developing fetus given its strong vasodilator actions.…”

Persistent insulin signaling coupled with restricted PI3K activation causes insulin-induced vasoconstriction

“…Vasomotor responses were expressed as percent vasodilation (i.e., the quotient of ⌬ diameter -baseline diameter and ⌬ maximal Ca 2ϩ free diameter -baseline diameter, multiplied by 100) or vasoconstriction (quotient of ⌬diameter -baseline diameter and baseline diameter). The area under (or over) the curve (net incremental; AUC) was calculated to approximate the net dilatory or constrictor response for each experimental condition (17,38).…”

Sildenafil: how to make a bad situation worse

“…2009; Inocencio et al . 2019; Inocencio et al . 2020) have provided strong evidence for the necessity of not only utilising a large animal model of human pregnancy complications in perinatal research but also in having these preclinical studies inform the choice to commence clinical trials.…”