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ItemPregnancy in aged rats that were born small: cardiorenal and metabolic adaptations and second-generation fetal growthGallo, LA ; Tran, M ; Moritz, KM ; Jefferies, AJ ; Wlodek, ME (FEDERATION AMER SOC EXP BIOL, 2012-10-01)Uteroplacental insufficiency is associated with adult cardiorenal and metabolic diseases, particularly in males. Pregnancy is the greatest physiological challenge facing women, and those born small are at increased risk of gestational hypertension and diabetes and delivering smaller babies. Increased maternal age is associated with exacerbated pregnancy complications. We hypothesized that pregnancy in aged, growth-restricted females unmasks an underlying predisposition to cardiorenal and metabolic dysfunction and compromises fetal growth. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (restricted group) or sham surgery (control group) on d 18 of gestation in Wistar Kyoto rats. At 12 mo, growth-restricted F1 female offspring were mated with a normal male. F1 restricted females had elevated systolic blood pressure, before and during pregnancy (+10 mmHg) but normal renal and metabolic pregnancy adaptations. F2 fetal weight was not different between groups. In control and restricted females, advanced maternal age (12 vs. 4 mo) was associated with a reduction in the hypoglycemic response to pregnancy and reduced F2 fetal litter size and body weight. Aged rats born small exhibited mostly normal pregnancy adaptations, although they had elevated blood pressure. Advanced maternal age was associated with poorer fetal outcomes that were not exacerbated by low maternal birth weight.
ItemUteroplacental Insufficiency and Lactational Environment Separately Influence Arterial Stiffness and Vascular Function in Adult Male RatsTare, M ; Parkington, HC ; Bubb, KJ ; Wlodek, ME (LIPPINCOTT WILLIAMS & WILKINS, 2012-08-01)Early life environmental influences can have lifelong consequences for health, including the risk of cardiovascular disease. Uteroplacental insufficiency causes fetal undernutrition and impairs fetal growth. Previously we have shown that uteroplacental insufficiency is associated with impaired maternal mammary development, compromising postnatal growth leading to hypertension in male rat offspring. In this study we investigated the roles of prenatal and postnatal nutritional environments on endothelial and smooth muscle reactivity and passive wall stiffness of resistance arteries of male rat offspring. Fetal growth restriction was induced by maternal bilateral uterine vessel ligation (restricted) on day 18 of pregnancy. Control offspring were from mothers that had sham surgery (control) and another group from mothers with their litter size reduced (reduced; litter size reduced to 5 at birth, equivalent to the restricted group). On postnatal day 1, offspring (control, restricted, and reduced) were cross-fostered onto control or restricted mothers. At 6 months, mesenteric and femoral arteries were studied using wire and pressure myography. In restricted-on-restricted rats, wall stiffness was increased, and sensitivity to phenylephrine and relaxation evoked by endothelium-derived hyperpolarizing factor and sodium nitroprusside were impaired in mesenteric arteries. In femoral arteries, relaxation to sodium nitroprusside was reduced, whereas wall stiffness was unaltered. Cross-fostering restricted offspring onto control mothers alleviated deficits in vascular stiffness and reactivity. Control or reduced offspring who suckled a restricted mother had marked vascular stiffening. In conclusion, prenatal and early postnatal environments separately influence vascular function and stiffness. Furthermore, the early postnatal lactational environment is a determinant of later cardiovascular function.
ItemEffect of Pregnancy for Females Born Small on Later Life Metabolic Disease RiskTran, M ; Gallo, LA ; Wadley, GD ; Jefferies, AJ ; Moritz, KM ; Wlodek, ME ; He, B (PUBLIC LIBRARY SCIENCE, 2012-09-13)There is a strong inverse relationship between a females own birth weight and her subsequent risk for gestational diabetes with increased risk of developing diabetes later in life. We have shown that growth restricted females develop loss of glucose tolerance during late pregnancy with normal pancreatic function. The aim of this study was to determine whether growth restricted females develop long-term impairment of metabolic control after an adverse pregnancy adaptation. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham surgery (Control) in late pregnancy (E18) in F0 female rats. F1 Control and Restricted female offspring were mated with normal males and allowed to deliver (termed Ex-Pregnant). Age-matched Control and Restricted Virgins were also studied and glucose tolerance and insulin secretion were determined. Pancreatic morphology and hepatic glycogen and triacylglycerol content were quantified respectively. Restricted females were born lighter than Control and remained lighter at all time points studied (p<0.05). Glucose tolerance, first phase insulin secretion and liver glycogen and triacylglycerol content were not different across groups, with no changes in β-cell mass. Second phase insulin secretion was reduced in Restricted Virgins (-34%, p<0.05) compared to Control Virgins, suggestive of enhanced peripheral insulin sensitivity but this was lost after pregnancy. Growth restriction was associated with enhanced basal hepatic insulin sensitivity, which may provide compensatory benefits to prevent adverse metabolic outcomes often associated with being born small. A prior pregnancy was associated with reduced hepatic insulin sensitivity with effects more pronounced in Controls than Restricted. Our data suggests that pregnancy ameliorates the enhanced peripheral insulin sensitivity in growth restricted females and has deleterious effects for hepatic insulin sensitivity, regardless of maternal birth weight.