Transgenerational left ventricular hypertrophy and hypertension in offspring after uteroplacental insufficiency in male rats

Abstract

Epidemiological studies have shown an association between low birthweight and adult disease development with transmission to subsequent generations. The aim of the present study was to examine the effect of intrauterine growth restriction in rats, induced by uteroplacental insufficiency, on cardiac structure, number, size, nuclearity, and adult blood pressure in first (F1) and second (F2) generation male offspring. Uteroplacental insufficiency or sham surgery was induced in F0 Wistar-Kyoto pregnant rats in late gestation giving rise to F1 restricted and control offspring, respectively. F1 control and restricted females were mated with normal males, resulting in F2 control and restricted offspring, respectively. F1 restricted male offspring were significantly lighter at birth (P < 0.05), but there were no differences in birthweight of F2 offspring. Left ventricular weights and volumes were significantly increased (P < 0.05) in F1 and F2 restricted offspring at day 35. Left ventricular cardiomyocyte number was not different in F1 and F2 restricted offspring. At 6 months-of-age, F1 and F2 restricted offspring had elevated blood pressure (8-15 mmHg, P < 0.05). Our findings demonstrate the emergence of left ventricular hypertrophy and hypertension, with no change in cardiomyocyte number, in F1 restricted male offspring, and this was transmitted to the F2 offspring. The findings support transgenerational programming effects.

Akt signaling as a mediator of cardiac adaptation to low birth weight

“…In humans, reduced growth before birth is also associated with altered left ventricular mass (Vijayakumar et al 1995), with intrauterine growth-restricted (IUGR) fetuses having a larger heart relative to their body weight (Veille et al 1993). Furthermore, the altered left ventricular hypertrophy was transmitted to the F2 offspring in rats, indicating transgenerational programming effects of IUGR (Master et al 2014). Left ventricular hypertrophy in adulthood is also associated with deleterious cardiovascular disease outcomes (Levy et al 1988(Levy et al , 1989(Levy et al , 1990, prompting studies to understand the molecular basis of this association and the impact on cardiac growth and maturation.…”

“…Therefore, any insults to the heart during this developmental transition period can have a lifelong effect, especially as cardiomyocytes begin withdrawing from the cell cycle at around the time of birth. In IUGR, there are fewer cardiomyocytes in the fetus and offspring (Stacy et al 2009, Black et al 2012 IUGR decreases cardiomyocyte endowment and the reduced number of cardiomyocytes in the heart are forced to undergo hypertrophy to maintain cardiac function (Morrison et al 2007, Black et al 2012, Botting et al 2014, Master et al 2014). Botting et al 2014), which may limit the potential of the heart to adapt to changes in supply of nutrients and oxygen in fetal life or to changes in load after birth.…”

Postnatal undernutrition alters adult female mouse cardiac structure and function leading to limited exercise capacity

“…; Master et al . ) and their capacity to recover appears to depend on the developmental stage at recovery (Bai et al . ; Lim et al .…”

“…Thus, the extent of cardiac maturation that occurs after birth will depend on the degree of prematurity, which could be substantial, and subject to the postnatal nutritional state. In sheep and rodents, newborns that experienced prenatal growth impairment have fewer cardiomyocytes (Corstius et al 2005;Stacy et al 2009;Master et al 2014) and their capacity to recover appears to depend on the developmental stage at recovery (Bai et al 1990;Lim et al 2010;Black et al 2012;Botting et al 2012;Vranas et al 2017). However, the extent to which alterations in cardiac cell size, number and nucleation/ploidy are impacted when a nutritional deficit occurs only after birth, i.e.…”

Primary Pediatric Hypertension: Current Understanding and Emerging Concepts

“…There are several models of utero-placental insufficiency, including ligation of either the ovarian or uterine arteries [106]. F1 and F2 male but not female offspring of Wistar-Kyoto rat dams with uteroplacental insufficiency caused by bilateral uterine vessel ligation developed hypertension at 6 months of age that could be related, in part, to impaired vasorelaxation and arterial stiffness, especially in the mesenteric artery [107, 108]. Female offspring which were not hypertensive had normal mesenteric, renal, and femoral artery stiffness but had uterine artery endothelial dysfunction and increased wall stiffness [109••].…”