Sex-specific effects of advanced maternal age on cardiovascular function in aged adult rat offspring

Abstract

Pregnancy at an advanced maternal age has an increased risk of complications for both the mothers and their offspring. We have previously shown that advanced maternal age in a rat model leads to poor fetal outcomes, maternal vascular dysfunction, and hypertension, concordant with findings in humans. Moreover, offspring from aged dams had sex-specific cardiovascular dysfunction in young adulthood. However, the detrimental impact of aging on the cardiovascular system of the offspring in this model is unknown. We hypothesized that offspring born to aged dams (9.5–10 mo old) would have impaired cardiovascular function at 12 mo of age. Echocardiographic data revealed signs of mild left ventricular diastolic dysfunction in only male offspring from aged dams [isovolumetric relaxation time: 34.27 ± 2.04 in the young dam group vs. 27.61 ± 0.99 ms in the aged dam group, P < 0.01; mitral annular velocity ratio ( E′/ A′): 1.08 ± 0.04 in the young dam group vs. 0.96 ± 0.02 in the aged dam group, P < 0.05]. We have previously shown that in young adulthood (4 mo of age), male, but not female, offspring born to aged dams had impaired recovery from ischemia-reperfusion injury. Aging did not alter the susceptibility of female offspring to ischemia-reperfusion injury. Interestingly, wire myography data revealed that male offspring from aged dams had enhanced vascular sensitivity to methacholine (negative log of EC50: 7.4 ± 0.08 in young dams vs. 7.9 ± 0.11 in aged dams, P = 0.007) due, in part, to increased prostaglandin-mediated vasodilation. Despite intact endothelium-dependent relaxation, female offspring from aged dams had elevated systolic blood pressure (125.3 ± 4.2 mmHg in young dams vs. 144.0 ± 6.9 mmHg in aged dams, P = 0.03). These data highlight sex-specific mechanisms underlying cardiovascular programming in offspring born to dams of advanced age. NEW & NOTEWORTHY Our study demonstrated that adult male and female offspring (12 mo old) born to aged dams had impaired cardiac diastolic function and increased blood pressure, respectively, signifying sex-specific differential cardiovascular effects of advanced maternal age.

Advanced maternal age compromises fetal growth and induces sex-specific changes in placental phenotype in rats

“…However, little information is available about whether advanced maternal age leads to any sex-specific changes in placental structure and functional capacity. Such sex-specific changes in placental phenotype may be linked to the early-life programming of cardiovascular disease susceptibility in offspring born of aged dams, which we have shown to be sex-dependent 23,24 .…”

“…Indeed, glucocorticoids can affect cardiomyocyte differentiation and induce oxidative stress in tissues including the heart and vasculature 70 . Even though fetal weight was similarly compromised for female and male fetuses from aged dams and both sexes experience postnatal catch up growth, we have previously found that adult male offspring of aged dams have a greater propensity to develop cardiovascular dysfunction as adults, when compared to female offspring 23,24 . Therefore, possible increases in glucocorticoid exposure of the male fetus, via decreased placental 11β-hsd2 may have contributed to the programming of cardiovascular dysfunction seen specifically in male offspring of aged dams.…”

“…Both female and male fetuses were similarly growth restricted, although absolute weight of male fetal heart, brain and liver were reduced in aged dams versus young dams. Moreover, our previous studies have shown poorer cardiovascular outcomes for adult male offspring from aged dams 24 . Taken together, our data demonstrate that the effects of advanced maternal age on fetal growth and also later-life offspring health may be mediated, at least in part, by sexually-dimorphic changes in the placenta during pregnancy.…”

Early Life Oxidative Stress and Long-Lasting Cardiovascular Effects on Offspring Conceived by Assisted Reproductive Technologies: A Review

“…From the maternal point of view, advanced maternal age (AMA) [ 154 , 155 ] and OS-increased ART-associated pregnancy complications (e.g., HDP [ 156 , 157 ], GDM [ 158 ], IUGR [ 159 ], and preterm birth [ 100 ]) are frequently associated with cardiovascular dysfunction in the offspring. For example, AMA/HDP/IUGR have been linked with increased blood pressure and/or altered cardiovascular function in offspring [ 154 , 155 , 156 , 159 ], while GDM/preterm birth have been linked with CVDs in offspring [ 100 , 158 ]. Specifically, in a mouse model, it was reported that AMA affects the phenotype of the offspring in a sex-dependent manner: in young adulthood (four months of age), male (but not female) offspring birthed by aged dams presented reperfusion injury and impaired endothelium-dependent relaxation.…”

“…Specifically, in a mouse model, it was reported that AMA affects the phenotype of the offspring in a sex-dependent manner: in young adulthood (four months of age), male (but not female) offspring birthed by aged dams presented reperfusion injury and impaired endothelium-dependent relaxation. In mature adulthood (12 months of age), female offspring showed increased systolic blood pressure, whereas male offspring showed decreased ventricular diastolic function and increased vascular sensitivity to methacholine [ 154 , 155 ].…”