Impact of diet on the persistence of early vascular remodeling and stiffening induced by intrauterine growth restriction and a maternal high-fat diet

Abstract

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.

Protective effect of antioxidants on cardiac function in adult offspring exposed to prenatal overnutrition

“…A recent study proposed that cardiac dysfunction in the offspring of HFD mothers could be the result of early adverse cardiovascular remodeling. 29 Taken together, these data indicate that the ultimate outcome of pathological cardiac changes programmed by fetal overnutrition is the impairment of heart function. A large proportion of women with obesity present with hyperglycemia and their offspring show signs of cardiovascular dysfunction.…”

Growth trajectory during the first 1000 days and later overweight in very preterm infants

“…The rise in BMI after hospital discharge, a reflection of the family environment, could result from exposure to a postdischarge challenge or ‘second insult’ constituted by familial environment, superimposed on the ‘first insult’ constituted by the initial challenge of postnatal nutrition of the preterm infants, as amply documented in low birthweight rodent models 22–24. Conversely, a decrease in BMI Z-score after hospital discharge may be a warning signal for risk of later UW.…”

Large artery stiffening and mortality in a rat model of early vascular remodeling induced by intrauterine growth restriction and a high‐fat diet

“…The University of Utah Animal Care and Use Committee approved all animal procedures. The rat model of IUGR and an HFD used in these studies was as previously described (Dodson et al, 2017 ; Miller et al, 2019 ; Zinkhan et al, 2016 ). In brief, fifty‐day‐old male and female Sprague Dawley CD rats were obtained from Charles River Laboratories, Inc (Wilmington, MA).…”

“…Because our study design resulted in a total of six diet and intrauterine condition groups, the large sample size precluded running all six samples per group on a single western blot gel. To address this challenge, sexes were run on separate gels and analyzed separately, and no statistical comparisons were made between sexes, as previously described (Miller et al, 2019 ). Within each sex, protein samples from all six CRR and IRR rats were run on every gel along with either all six samples from both CHR and IHR or both CHH and IHH rats.…”

“…In our previous studies using a rat model of IUGR combined with a maternal and post‐weaning high‐fat diet, we demonstrate the importance of developmental programming in the evolution of hypertension, hyperlipidemia, and changes to the extracellular matrix (ECM) early in life (Dodson et al, 2017 ; Miller et al, 2019 ; Zinkhan et al, 2016 ). This study aims to evaluate the persistence of these early‐life changes with aging in 12‐month‐old rats.…”