Maternal undernutrition and developmental programming of cardiovascular and metabolic disorders in male offspring. The impact of neonatal GH treatment

Abstract

Background An adverse intrauterine or neonatal environment is often associated with increased blood pressure and cardiovascular disease in offspring. Recent evidence in animal models suggests that maternal undernutrition, in addition to eliciting an inflammatory phenotype in the mother, leads to a pro-inflammatory phenotype in the offspring at birth. Further, there is some evidence that treatment of offspring with growth hormone (GH) during the pre-weaning period can prevent the development of later life high blood pressure. However, the mechanisms are yet to be elucidated. The aim of this study is to determine whether inflammatory pathways, immune cell infiltration and endothelial dysfunction in the kidney are involved in the programming of hypertension in a validated small animal model of maternal undernutrition and whether GH treatment can attenuate these effects. Methods Female Sprague-Dawley rats were fed either a standard control diet (CON) or 50% of CON intake throughout pregnancy (UN). All dams were fed ad libitum throughout lactation. From neonatal day 3 until weaning (day 21), CON and UN pups were treated with either saline (CON-S, UN-S) or GH (2.5 μg/g/day) (CON-GH, UN-GH). After weaning, male offspring were fed a standard diet until the end of the study. Systolic blood pressure (SBP) was measured at day 150 by tail cuff plethysmography. Quantitative reverse transcription polymerase chain reaction was used to determine renal mRNA levels for the monocytes/macrophages marker CD68, monocyte chemoattractant protein (MCP-1), CD11c, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL12p35, transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor-α (VEGF-α), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 1-3 (IGFBP) in all four offspring groups. Results and Conclusions Maternal UN induced hypertension in the UN-S offspring, which was normalised with preweaning GH treatment. Maternal UN increased circulating pro-inflammatory markers in the UN-S offspring and were normalised with GH treatment. Gene expression of TNF-α, MCP-1 were increased by maternal UN and IL-12p35 and VEGF-α mRNA expression was upregulated by GH treatment. Renal mRNA expression of the adhesion molecules ICAM-1 and VCAM-1 were upregulated in the UN-S group and normalised in the UN-GH group. Analyses of renal function using plasma parameters indicated impaired renal function in the UN-S group; there was also evidence of renal hypertrophy in the UN-S group. However renal histopathologic evaluation revealed no obvious signs of damage or leukocyte infiltration. These findings indicate that metabolic and cardiovascular health is significantly affected by maternal UN and pre-weaning GH treatment has the potential to normalise some of the adverse cardiovascular sequalae that arise as a consequence of poor maternal nutrition. The results presented in this thesis demonstrate that this may be mediated in part by beneficial effects of GH on renal function.