Cardio-renal and metabolic adaptations during pregnancy in female rats born small: implications for maternal health and second generation fetal growth

Abstract

Intrauterine growth restriction caused by uteroplacental insufficiency increases risk of cardiovascular and metabolic disease in offspring. Cardio-renal and metabolic responses to pregnancy are critical determinants of immediate and long-term maternal health. However, no studies to date have investigated the renal and metabolic adaptations in growth restricted offspring when they in turn become pregnant. We hypothesised that the physiological challenge of pregnancy in growth restricted females exacerbates disease outcome and compromises next generation fetal growth. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham surgery (Control) on day 18 of gestation in WKY rats and F1 female offspring birth and postnatal body weights were recorded. F1 Control and Restricted females were mated at 4 months and blood pressure, renal and metabolic parameters were measured in late pregnancy and F2 fetal and placental weights recorded. Age-matched non-pregnant Control and Restricted F1 females were also studied. F1 Restricted females were born 10-15% lighter than Controls. Basal insulin secretion and pancreatic β-cell mass were reduced in non-pregnant Restricted females but restored in pregnancy. Pregnant Restricted females, however, showed impaired glucose tolerance and compensatory glomerular hypertrophy, with a nephron deficit but normal renal function and blood pressure. F2 fetuses from Restricted mothers exposed to physiological measures during pregnancy were lighter than Controls highlighting additive adverse effects when mothers born small experience stress during pregnancy. Female rats born small exhibit mostly normal cardio-renal adaptations but altered glucose control during late pregnancy making them vulnerable to lifestyle challenges.

Figure 1. Plasma insulin and glucose prior to and in response to IPGTT

Measurements from non-pregnant and pregnant (E18) animals (mean ± SEM; n= 8–10/group). †P < 0.05 vs. non-pregnant (main effect); ‡P < 0.05 vs. non-pregnant Control; §P < 0.05 vs. pregnant Control (following significant interaction); ¶P < 0.05 vs. non-pregnant Restricted (following significant interaction).

Figure 2. Pancreatic β-cell mass and islet proprtion per pancreas

Measurements from non-pregnant and pregnant (E20) animals (mean ± SEM; n= 6–7/group). ‡P < 0.05 vs. non-pregnant Control (following significant interaction).

Figure 3. Total glomerular number, and individual and total glomerular volume

Measurements from pregnant (E20) animals (mean ± SEM; n= 5/group). *P < 0.05 vs. Control.

Figure 4. F2 fetal body and placental weights

Measurements in offspring from pregnant 1 (E20) and pregnant 2 (E20) animals and averaged per sex per litter (mean ± SEM; n= 9–11 litters/group). *P < 0.05 vs. Control (main effect); †P < 0.05 vs. males (main effect); ††P < 0.05 vs. pregnant 1 (right vs. left panel within gender; main effect).