Increased susceptibility to cardiovascular disease in offspring born from dams of advanced maternal age

Abstract

Key points: Advanced maternal age increases the risk of pregnancy complications such as fetal growth restriction, hypertension and premature birth. Offspring born from compromised pregnancies are at increased risk of cardiovascular disease as adults. However, the effect of advanced maternal age on later-onset disease in offspring has not been investigated. In adulthood, male but not female offspring born to dams of advanced maternal age showed impaired recovery from cardiac ischaemia/reperfusion injury. Endothelium-dependent relaxation was also impaired in male but not female offspring born from aged dams. Oxidative stress may play a role in the developmental programming of cardiovascular disease in this model. Given the increasing trend toward delayed parenthood, these findings have significant population and health care implications and warrant further investigation.

Abstract: Exposure to prenatal stressors, including hypoxia, micro- and macronutrient deficiency, and maternal stress, increases the risk of cardiovascular disease in adulthood. It is unclear whether being born from a mother of advanced maternal age (≥35 years old) may also constitute a prenatal stress with cardiovascular consequences in adulthood. We previously demonstrated growth restriction in fetuses from a rat model of advanced maternal age, suggesting exposure to a compromised in utero environment. Thus, we hypothesized that male and female offspring from aged dams would exhibit impaired cardiovascular function as adults. In 4-month-old offspring, we observed impaired endothelium-dependent relaxation in male (P < 0.05) but not female offspring born from aged dams. The anti-oxidant polyethylene glycol superoxide dismutase improved relaxation only in arteries from male offspring of aged dams (ΔE_max : young dam -1.63 ± 0.80 vs. aged dam 11.75 ± 4.23, P < 0.05). Furthermore, endothelium-derived hyperpolarization-dependent relaxation was reduced in male but not female offspring of aged dams (P < 0.05). Interestingly, there was a significant increase in nitric oxide contribution to relaxation in females born from aged dams (ΔE_max : young dam -24.8 ± 12.1 vs. aged dam -68.7 ± 7.7, P < 0.05), which was not observed in males. Recovery of cardiac function following an ischaemia-reperfusion insult in male offspring born from aged dams was reduced by ∼57% (P < 0.001), an effect that was not evident in female offspring. These data indicate that offspring born from aged dams have an altered cardiovascular risk profile that is sex-specific. Given the increasing trend toward delaying pregnancy, these findings may have significant population and health care implications and warrant further investigation.

Keywords: advanced maternal age; cardiovascular dysfunction; developmental programming.

Figure 1

Endothelium‐dependent relaxation in male and female offspring from young and aged dams Maximal endothelium‐dependent relaxation in response to methylcholine was impaired in mesenteric arteries in male (A) but not female (B) offspring born from aged compared to young dams. Inset: summary E _max data. ^** P < 0.01 using Student's t test (n = 6–10 per group)

Figure 2

Role of oxidative stress, NOS‐ and EDH‐dependent pathways on maximal relaxation in vessels from male and female offspring Effect of superoxide anion scavenging (A and D) and inhibition of NO production (B and E) or EDH (C and F) on vascular relaxation in mesenteric arteries from male and female offspring from young and aged dams. Data are analysed as the ΔE _max of MCh responses with or without inhibitor. Pre‐incubation with the anti‐oxidant pegSOD improved endothelium‐dependent relaxation in male but not female offspring from aged dams. Inhibition of NOS demonstrated an increased contribution of NO to relaxation in female but not male offspring. Inhibition of small and large conductance calcium activated potassium channels demonstrated a reduced contribution of EDH to relaxation in male but not female offspring of aged dams. ^** P < 0.01 using Student's t test (n = 6–10 per group)

Figure 3

Role of thromboxane receptors in endothelium‐dependent relaxation Prostaglandin‐derived constriction on vascular function in mesenteric arteries from male (A and C) and female (B and D) offspring from young and aged dams. Pre‐incubation with the thromboxane receptor inhibitor SQ29548 improved vascular relaxation in both male and female offspring. However, analysis of the pEC₅₀ values demonstrated that there was an enhanced sensitivity to thromboxane receptor blockade in male offspring from aged dams. There was no significant effect of dam age on pEC₅₀ values in female offspring. Two‐way ANOVA. ^** P < 0.01, ^**** P < 0.001 of group effect, post hoc analysis; different lowercase letters indicate a statistically significant difference, P < 0.05 (n = 6–10 per group)

Figure 4

Molecular characterization of mesenteric arteries from male and female offspring born from young and aged dams Analysis of oxidative stress via DHE staining in mesenteric arteries from (A) male and (D) female offspring demonstrated no significant differences with maternal age. Protein levels of eNOS were unaltered in (B) male or (E) female offspring. Protein levels of PGHS1 tended to be increased in (C) male offspring from aged dams but not in (F) female offspring. Blots were quantitated using Odyssey software. Data were collected as triplicates for each sample and were normalized to α‐tubulin. All groups were compared using Student's t test (n = 4–5 per group)

Figure 5. Ex vivo assessment of cardiac function after I/R injury using the Langendorff heart system in male and female offspring from young and aged dams

Absolute cardiac power and percent change of reperfusion cardiac power after I/R are shown in male (A and C) and female (B and D) offspring. ^*** P < 0.001 using Student's t test; isch, ischaemia (n = 5 per group)

Figure 6

Molecular characterization of left ventricular tissue from male and female offspring born from young and aged dams Analysis of oxidative stress via DHE staining in cardiac LV tissue after I/R injury in male (A) and female (C) offspring. Superoxide levels were significantly increased in female but not male offspring. Data are expressed as the mean intensity per cell normalized to the young dam control. Cardiac SERCA2a protein levels were unaltered by maternal age in male (B) and female (D) offspring. ***P < 0.001 using Student's t test (n = 5 per group)