Abstract
Fetal growth restriction (FGR) affects 3–8% of human pregnancies. Mouse models have provided important etiological data on FGR; they permit the assessment of treatment strategies on the physiological function of both mother and her developing offspring. Our study aimed to 1) develop a method to assess vascular function in fetal mice and 2) as a proof of principle ascertain whether a high dose of sildenafil citrate (SC; Viagra) administered to the pregnant dam affected fetal vascular reactivity. We developed a wire myography methodology for evaluation of fetal vascular function in vitro using the placenta-specific insulin-like growth factor II (Igf2) knockout mouse (P0; a model of FGR). Vascular function was determined in abdominal aortas isolated from P0 and wild-type (WT) fetuses at embryonic day (E) 18.5 of gestation. A subset of dams received SC 0.8 mg/ml via drinking water from E12.5; data were compared with water-only controls. Using wire myography, we found that fetal aortic rings exhibited significant agonist-induced contraction, and endothelium-dependent and endothelium-independent relaxation. Sex-specific alterations in reactivity were noted in both strains. Maternal treatment with SC significantly attenuated endothelium-dependent and endothelium-independent relaxation of fetal aortic rings. Mouse fetal abdominal aortas reproducibly respond to vasoactive agents. Study of these vessels in mouse genetic models of pregnancy complications may 1) help to delineate early signs of abnormal vascular reactivity and 2) inform whether treatments given to the mother during pregnancy may impact upon fetal vascular function.
Highlights
FETAL GROWTH RESTRICTION (FGR) is a major pregnancy problem affecting 8% of births in the United Kingdom (46)
Mouse models that exhibit FGR include the endothelial nitric oxide synthase knockout mouse (18, 43) and the placenta-specific Igf[2] knockout (P0) mouse (2, 16), in which 93% of P0 fetuses fall below the 5th percentile of C57BL6/J wild-type (WT) weights at term (8)
Heterozygous males with the P0 deletion were mated with C57BL6/J female mice (WT; 6 –10 wk of age; presence of copulation plug was considered E0.5; term was considered E19.5), which resulted in mixed litters consisting of both WT and P0 fetuses
Summary
FETAL GROWTH RESTRICTION (FGR) is a major pregnancy problem affecting 8% of births in the United Kingdom (46). Stanley et al (39) described similar waveform patterns in uterine arteries of Leprdb/ϩ mice, which spontaneously develop gestational diabetes mellitus (GDM) (39); interestingly, reduced peak systolic and enddiastolic velocity and increased resistance indices in heterozygous mice suggest reduced uterine perfusion in diabetic animals. These in vivo assessments, suggesting similar hemodynamics in mouse and human pregnancies, have been supported by in vitro studies. In pregnant C57BL6/J mice, we have extended these studies to assess fetal umbilical arterial and venous vascular reactivity (15) All of these reports support the in vivo evidence of increased uterine perfusion during mouse pregnancy, as occurs in women. Statin therapy for pregnancy complications has been assessed; pravastatin administration potentially prevented placental damage and protected pregnancies in a model of recurrent spontaneous miscarriage (DBA/2-mated CBA/J mice) (31) and may ameliorate disease symptoms in a mouse model of
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