RESUMEN
Intrauterine growth restriction (IUGR) and maternal high-fat diet (HFD) independently predispose offspring to hypertension. In a rat model, IUGR more so than maternal HFD increases arterial stiffness with vascular remodeling as early as postnatal day (PND) 21. The trajectory of such early vascular changes remains unknown. We hypothesized that IUGR would increase blood pressure (BP), arterial stiffness, and markers of ongoing detrimental vascular remodeling in adult rats exposed to a maternal HFD regardless of weaning diet. Adult female rats were fed either a regular diet (RD) or an HFD before mating through lactation. IUGR was induced by uterine artery ligation. Offspring were weaned to either a RD or HFD through PND 60. For both control and IUGR rats, this design resulted in the following three diet groups: offspring from RD dams weaned to a RD and offspring from HFD dams weaned to a RD or to an HFD (IHH). In both males and females, only IHH increased systolic BP, but IUGR and HFD both alone and in combination increased arterial stiffness. Aortas contained fewer but thicker elastin bands in IHH rats and IUGR offspring from dams fed an HFD and weaned to a regular diet. IHH increased aortic lysl oxidase protein. In summary, the PND 21 rat mediators of vascular remodeling from IUGR and maternal HFD normalize by PND 60 while changes in elastin and arterial stiffness persist. We speculate that the longer-term risk of hypertension from dietary mediators is augmented by underlying IUGR-induced structural changes to the extracellular matrix.NEW & NOTEWORTHY We report that a combined insult of intrauterine growth restriction and maternal high-fat diet increases the risk of early cardiovascular pathology both independently and in conjunction with a continued high-fat diet in offspring.
Asunto(s)
Aorta Abdominal/fisiopatología , Dieta Alta en Grasa , Retardo del Crecimiento Fetal/fisiopatología , Fenómenos Fisiologicos Nutricionales Maternos , Efectos Tardíos de la Exposición Prenatal , Remodelación Vascular , Rigidez Vascular , Factores de Edad , Animales , Aorta Abdominal/metabolismo , Presión Arterial , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Femenino , Retardo del Crecimiento Fetal/metabolismo , Masculino , Estado Nutricional , Embarazo , Ratas Sprague-Dawley , Factores SexualesRESUMEN
Intrauterine growth restriction (IUGR) in premature newborns increases the risk for bronchopulmonary dysplasia, a chronic lung disease characterized by disrupted pulmonary angiogenesis and alveolarization. We previously showed that experimental IUGR impairs angiogenesis; however, mechanisms that impair pulmonary artery endothelial cell (PAEC) function are uncertain. The NF-κB pathway promotes vascular growth in the developing mouse lung, and we hypothesized that IUGR disrupts NF-κB-regulated proangiogenic targets in fetal PAEC. PAECs were isolated from the lungs of control fetal sheep and sheep with experimental IUGR from an established model of chronic placental insufficiency. Microarray analysis identified suppression of NF-κB signaling and significant alterations in extracellular matrix (ECM) pathways in IUGR PAEC, including decreases in collagen 4α1 and laminin α4, components of the basement membrane and putative NF-κB targets. In comparison with controls, immunostaining of active NF-κB complexes, NF-κB-DNA binding, baseline expression of NF-κB subunits p65 and p50, and LPS-mediated inducible activation of NF-κB signaling were decreased in IUGR PAEC. Although pharmacological NF-κB inhibition did not affect angiogenic function in IUGR PAEC, angiogenic function of control PAEC was reduced to a similar degree as that observed in IUGR PAEC. These data identify reductions in endothelial NF-κB signaling as central to the disrupted angiogenesis observed in IUGR, likely by impairing both intrinsic PAEC angiogenic function and NF-κB-mediated regulation of ECM components necessary for vascular development. These data further suggest that strategies that preserve endothelial NF-κB activation may be useful in lung diseases marked by disrupted angiogenesis such as IUGR.
Asunto(s)
Displasia Broncopulmonar , Células Endoteliales , Retardo del Crecimiento Fetal , Subunidad p50 de NF-kappa B/metabolismo , Arteria Pulmonar , Transducción de Señal , Factor de Transcripción ReIA/metabolismo , Animales , Displasia Broncopulmonar/inducido químicamente , Displasia Broncopulmonar/embriología , Displasia Broncopulmonar/patología , Displasia Broncopulmonar/fisiopatología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Femenino , Retardo del Crecimiento Fetal/inducido químicamente , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/patología , Retardo del Crecimiento Fetal/fisiopatología , Lipopolisacáridos/toxicidad , Embarazo , Arteria Pulmonar/embriología , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , OvinosRESUMEN
Accurate mouse sexing is vital when conducting research examining sexual dimorphisms. Late fetal and newborn mouse pups are more immature than many previously described sexing methods allow. This study compares the sexing accuracy of a newly described internal gonad sexing method to a recently described peritoneal pigmentation sexing method in embryonic day 20 C57BL/6J mouse pups, using Sry genotyping to confirm the sex. The internal gonad sexing method was found to be highly accurate, while the peritoneal pigmentation method was slightly less accurate. Therefore, while Sry genotyping remains the gold standard, immediate and less expensive sexing methods can be performed accurately as early as the late fetal period in C57BL/6J mice.
Asunto(s)
Ratones Endogámicos C57BL/anatomía & histología , Animales , Embrión de Mamíferos/anatomía & histología , Femenino , Genes sry , Genitales/anatomía & histología , Genitales/embriología , Técnicas de Genotipaje/veterinaria , Masculino , Ratones Endogámicos C57BL/embriología , Ratones Endogámicos C57BL/genética , Pigmentación , Reproducibilidad de los Resultados , Caracteres Sexuales , Análisis para Determinación del Sexo/métodos , Análisis para Determinación del Sexo/veterinariaRESUMEN
High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intra-amniotic injections of ETX, ETX+vit D, or saline at 20 days gestation (term = 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased α-elastin, lysyl oxidase, collagen I, and collagen III proteins (P < 0.05) compared control and ETX+vit D lungs. ETX-exposed animals have increased RV mechanical stroke work (P < 0.05 vs. control and ETX+vit D) and elastic potential energy (P < 0.05 vs. control and ETX+vit D). Mechanical stiffness and ECM remodeling are increased in the PA (P < 0.05 vs. control and ETX+vit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment.