Effect of intrauterine fetal programming on response to postnatal shaker stress in endothelial nitric oxide knockout mouse model

Abstract

Objective: To determine whether the intrauterine environment affects the postnatal vascular response to stress in a model of fetal programming induced by endothelial nitric oxide synthase deficiency.

Study design: Homozygous nitric oxide synthase knockout and wild-type controls were crossbred to obtain maternally and paternally derived heterozygous offspring. At 14 weeks of age, in vivo blood pressure measurements by telemetry, and in vitro carotid arteries vascular reactivity studies were performed in male offspring after subjecting them to shaker stress.

Results: Maternally derived heterozygous offspring, compared with paternally derived heterozygous offspring, had significantly higher systolic blood pressure, mean arterial blood pressure, and pulse pressure before, as well as after introduction of the shaker stress. The difference in the latter between maternally and paternally derived heterozygous offspring was accentuated after stress. Maternally derived heterozygous offspring also had significantly higher contractile responses to phenylephrine when compared with paternally derived heterozygous offspring, and this was abolished after incubation with L-NAME.

Conclusion: The adverse uterine environment affects the postnatal vascular response to stress.

Figure 1

Mean and SEM of daily systolic blood pressure in maternally- (KOM) and paternally- (KOP) derived male heterozygous offspring at 14 weeks of age. Blood pressure was measured in the carotid artery before and after introduction of stress stimuli (large arrow) (n=8–9 mice per group).

Figure 2

Mean and SEM of daily diastolic blood pressure in maternally- (KOM) and paternally- (KOP) derived male heterozygous offspring at 14 weeks of age. Blood pressure was measured in the carotid artery before and after introduction of stress stimuli (large arrow) (n=8–9 mice per group).

Figure 3

Mean and SEM of daily mean arterial blood pressure in maternally- (KOM) and paternally- (KOP) derived male heterozygous offspring at 14 weeks of age. Blood pressure was measured in the carotid artery before and after introduction of stress stimuli (large arrow) (n=8–9 mice per group).

Figure 4

Mean and SEM of daily pulse pressure in maternally- (KOM) and paternally- (KOP) derived male heterozygous offspring at 14 weeks of age. Blood pressure was measured in the carotid artery before and after introduction of stress stimuli (large arrow) (n=8–9 mice per group).

Figure 5

Concentration-response curves to phenylephrine (PE, 10⁻¹⁰–10⁻⁵ M) in the carotid artery of maternally- (KOM) and paternally- (KOP) derived male heterozygous offspring exposed to shaker stress at 14 weeks of age (n=8–12 mice per group).

Figure 6

Concentration-response curves to phenylephrine (PE, 10⁻¹⁰–10⁻⁵ M) in the presence of L-NAME in the carotid artery of maternally- (KOM) and paternally- (KOP) derived male heterozygous offspring exposed to shaker stress at 14 weeks of age (n=8–12 mice per group).

Figure 7

Relaxation-response curves to sodium nitroprusside (SNP, 10⁻¹⁰–10⁻⁵ M) in the carotid artery of maternally- (KOM) and paternally (KOP) derived male heterozygous offspring exposed to shaker stress at 14 weeks of age (n=8–12 mice per group).

Figure 8

Differences in contractile response to phenylephrine in the carotid artery of maternally- (KOM) and paternally (KOP) derived male heterozygous offspring exposed or not to shaker stress at 14 weeks of age (n=8–12 mice per group).