RESUMO
Fetal growth restriction (FGR), where a fetus fails to reach its genetic growth potential, affects up to 8% of pregnancies and is a major risk factor for stillbirth and adulthood morbidity. There are currently no treatments for FGR, but candidate therapies include the phosphodiesterase-5 inhibitor sildenafil citrate (SC). Randomized clinical trials in women demonstrated no effect of SC on fetal growth in cases of severe early onset FGR; however, long-term health outcomes on the offspring are unknown. This study aimed to assess the effect of antenatal SC treatment on metabolic and cardiovascular health in offspring by assessing postnatal weight gain, glucose tolerance, systolic blood pressure, and resistance artery function in a mouse model of FGR, the placental-specific insulin-like growth factor 2 (PO) knockout mouse. SC was administered subcutaneously (10 mg/kg) daily from embryonic day (E)12.5. Antenatal SC treatment did not alter fetal weight or viability but increased postnatal weight gain in wild-type (WT) female offspring (P < 0.05) and reduced glucose sensitivity in both WT (P < 0.01) and P0 (P < 0.05) female offspring compared with controls. Antenatal SC treatment increased systolic blood pressure in both male (WT vs. WT-SC: 117 ± 2 vs. 140 ± 3 mmHg, P < 0.0001; P0 vs. P0-SC: 113 ± 3 vs. 140 ± 4 mmHg, P < 0.0001; means ± SE) and female (WT vs. WT-SC: 121 ± 2 vs. 140 ± 2 mmHg, P < 0.0001; P0 vs. P0-SC: 117 ± 2 vs. 144 ± 4 mmHg, P < 0.0001) offspring at 8 and 13 wk of age. Increased systolic blood pressure was not attributed to altered mesenteric artery function. In utero exposure to SC may result in metabolic dysfunction and elevated blood pressure in later life.NEW & NOTEWORTHY Sildenafil citrate (SC) is currently used to treat fetal growth restriction (FGR). We demonstrate that SC is ineffective at treating FGR, and leads to a substantial increase systolic blood pressure and alterations in glucose homeostasis in offspring. We therefore urge caution and suggest that further studies are required to assess the safety and efficacy of SC in utero, in addition to the implications on long-term health.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Retardo do Crescimento Fetal/tratamento farmacológico , Fator de Crescimento Insulin-Like II/genética , Citrato de Sildenafila/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Peso ao Nascer , Feminino , Retardo do Crescimento Fetal/genética , Teste de Tolerância a Glucose , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Circulação Esplâncnica/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacosRESUMO
We tested the hypothesis that crossing two mouse models of fetal growth restriction (FGR) of differing phenotype would induce more severe FGR than either model alone. Female endothelial nitric oxide synthase knockout mice (eNOS(-/-)) were mated with placental-specific Igf2 knockout males (P0). Resultant fetuses were no more growth restricted than those with P0 deletion alone. However, P0 deletion attenuated the reduced placental system A amino acid transporter activity previously observed in eNOS(-/-) mice. Manipulating maternal and fetal genotypes provides a means to compare maternal and fetal regulation of fetal growth.
Assuntos
Modelos Animais de Doenças , Retardo do Crescimento Fetal/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Placenta/metabolismo , Sistema A de Transporte de Aminoácidos/metabolismo , Animais , Cruzamentos Genéticos , Feminino , Retardo do Crescimento Fetal/enzimologia , Retardo do Crescimento Fetal/patologia , Retardo do Crescimento Fetal/fisiopatologia , Peso Fetal , Heterozigoto , Homozigoto , Fator de Crescimento Insulin-Like II/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/genética , Tamanho do Órgão , Especificidade de Órgãos , Placenta/enzimologia , Placenta/patologia , Gravidez , Índice de Gravidade de DoençaRESUMO
The increasing number of mouse models of fetal growth restriction (FGR) make it crucial to standardize the way FGR is defined. By constructing growth curves in the placental-specific Igf2 knockout mouse (P0) it was demonstrated that 93% of P0 fetuses fell below the 5th centile of wild-type weights at E18.5, up from 44% at E16.5. This analysis, coupled with anthropomorphic measurements showing evidence of head sparing in P0 fetuses, allows clinical comparisons of FGR in mice through the use of clinically relevant growth curves. We suggest this as a standardized approach to defining FGR in mouse, and other animal models.
