Low birth weight followed by postnatal over‐nutrition in the guinea pig exposes a predominant player in the development of vascular dysfunction

Abstract

Key pointsr Suboptimal intrauterine conditions and consequent intrauterine growth reduction (IUGR), resulting in low birth weight (LBW), increase the risk for hypertension and cardiovascular disease in adulthood.r LBW offspring who experience an accelerated growth in childhood have a higher risk of cardiovascular disease than those who grow more slowly, suggesting that the postnatal environment interacts with programmed deficits in organ function to influence disease risk.r We show here that arterial stiffening in LBW guinea pig offspring is exacerbated with postnatal feeding of a Western diet, suggesting that IUGR confers heightened vascular susceptibility to postnatal risk factors and thus may contribute to an individual's total risk score.r Our results also demonstrate that the independent effect of the intrauterine environment on vascular function in young adult guinea pigs is greater than the effect of a postnatal Western diet, thus highlighting the importance of prenatal factors on long-term vascular health.Abstract The association between intrauterine growth restriction (IUGR) and hypertension is well established, yet the interaction between IUGR and other pathogenic contributors remains ill-defined. This study examined the independent and interactive effects of fetal growth reduction resulting in low birth weight (LBW), and postnatal Western diet (WD) on vascular function. Growth reduction was induced in pregnant guinea pigs by uterine artery ablation. LBW and normal birth weight (NBW) offspring were randomly assigned to a control diet (CD) or a WD. In young adulthood, length-tension curves were generated in aortic rings and responses to methacholine (MCh) were evaluated in the carotid and aorta using wire myography. Relative to NBW/CD, aortae of NBW/WD offspring were stiffer, as determined by a leftward shift in the length-tension curve, yet the shift in the LBW/CD curve was considerably greater. Aortic stiffening was most severe in LBW/WD (slope: NBW/CD, 1.97 ± 0.04; NBW/WD, 2.16 ± 0.04; LBW/CD, 2.28 ± 0.05; LBW/WD, 2.34 ± 0.07). Maximal responses (E max ) to MCh were significantly blunted in the aorta of LBW/CD vs. NBW/CD (P < 0.05) and in LBW/WD vs. NBW/WD offspring (P < 0.05); but WD alone had no influence on MCh responses. E max values for carotid responses to MCh were reduced in LBW/CD vs. NBW/CD (P < 0.05). Thus, aortic stiffening was influenced more by LBW than by a postnatal WD and the most severe stiffening was observed in LBW/WD offspring. In contrast, blunted endothelial responses in LBW/CD offspring were not exacerbated by WD. IUGR may have a greater independent impact on vascular function than a postnatal WD.

Adult vascular dysfunction in foetal growth‐restricted guinea‐pigs is associated with a neonate‐adult switching in Nos3 DNA methylation

“…Nonetheless, neonates from the FGR group showed markers of an impaired intrauterine growth at birth, as suggested by shorter hindlimb bones and the asymmetry between the head circumference and abdominal circumference. Similar results have been reported elsewhere in young adult FGR guinea‐pigs, effects that were partially reverted by the NAC treatment. This impaired foetal growth was projected at short‐term by a reduced post‐natal weight gain, as well as a reduced abdominal circumference as adults (8‐month‐old).…”

Impact of birth weight and postnatal diet on the gut microbiota of young adult guinea pigs

“…The model utilizes a combination of uterine artery ablation to induce LBW offspring, with a postnatal diet high in total fat and sugar, and produces a non-overweight phenotype with impaired vascular function, increased visceral adiposity, and liver fibrosis with fatty infiltration of the liver, hallmarks of metabolic disease (Sarr et al, 2014; Sarr et al, 2015; Thompson et al, 2014). …”

“…Chow-fed pregnant guinea pigs underwent uterine artery ablation (UAA) surgery at mid gestation (∼32 days, term 69 days) to generate normal and low birth weight offspring (NBW and LBW, respectively) due to chronic placental insufficiency as described previously (Turner & Trudinger, 2009; Sarr et al, 2014; Thompson et al, 2014). Sows delivered spontaneously at term (∼67 days) and birth weight was recorded.…”

“…Five days prior to weaning the postnatal control diet (CD, TD: 110240; Harlan Laboratories, Madison, WI, USA) was introduced to the pups through the maternal feeding tray. At 15 days of age the offspring were weaned, separated by sex, weighed, housed in individual cages, and randomized to either CD or a Western diet (WD, WD: 110239; Harlan Laboratories), as described previously (Thompson et al, 2014). Briefly, the diets differed in kilocalorie density (3.4 vs 4.2 kcal g −1 ), but were matched for protein and macronutrients.…”

“…Guinea pigs have been used interdependently in the study of in utero growth, fetal development, and the impact diet has on postnatal growth (Fernandez & Volek, 2006; Sarr et al, 2014; Sarr et al, 2015; Thompson et al, 2014). A limited number of studies have described the guinea pig intestinal microbiota and have highlighted an overlap of phyla present in both the guinea pig and human GIT (Yanabe et al, 2001; Takahashi et al, 2005; Hildebrand et al, 2012).…”