Long-term sex-specific consequences of prenatal hypoxia on systemic hemodynamics and baroreflex sensitivity in rats

Background Intrauterine hypoxia is a common pregnancy complication that programs long-term cardiovascular dysfunction. However, stage-specific effects on cardiac vs. vascular mechanisms remain incompletely understood. Aim We investigated baroreflex coefficient (BRC) and cardiac reactivity in peripubertal and adult rats exposed to acute hypobaric hypoxia at different gestational stages, examined autonomic mechanisms, and differentiated between cardiac and vascular components of the programed phenotype. Methods Pregnant Wistar rats were exposed to hypoxia on gestational day 10 (early organogenesis) or day 20 (late gestation). In offspring (PH10 or PH20) at 7 weeks and 3 months of age, femoral arterial and venous catheters were implanted. BRC was assessed using sodium nitroprusside (4.5 μg/kg) and phenylephrine (2 μg/kg). Autonomic contributions were evaluated with atropine (1 mg/kg) and atenolol (1 mg/kg). Additionally, cardiac morphometry and invasive left ventricular (LV) pressure indices were assessed to distinguish structural from functional cardiac alterations. Results PH10 offspring exhibited sustained tachycardia and moderate hypotension in the peripubertal period. In adulthood, sex-specific effects emerged: PH10 males displayed tachycardia (+11%, p < 0.05) and loss of baroreflex asymmetry, whereas PH10 females showed reduced mean arterial pressure (−9.6%, p < 0.05) with preserved reflex asymmetry. Atropine blockade revealed tachycardia was primarily due to vagal withdrawal, with an additional sympathetic component in males. Complete autonomic blockade (atropine + atenolol) eliminated all intergroup and sex-related differences in heart rate and BRC, indicating a predominantly autonomic origin. However, hypotension in females persisted under complete blockade, suggesting vascular component. Moreover, invasive hemodynamic assessment and heart weight measurements revealed distinct cardiac phenotypes depending on gestational stage and sex, with dichotomy in males: PH10 showed structural remodeling without functional impairment, whereas PH20 exhibited reduced indices of LV systolic performance without structural changes, which may contribute to the observed tachycardia. In females of both groups, cardiac function remained preserved despite hypotension, consistent with vascular origin. Conclusion Prenatal hypoxia programs distinct phenotypes depending on gestational stage: early organogenesis affects autonomic and vascular regulation, with no evidence of altered central baroreflex integration, whereas late gestation reduces load-dependent indices of LV systolic performance, particularly in males, while heart weight indices remain unchanged. The key mechanism appears to be reduced vagal tone, which masks underlying vascular reactivity; tachycardia was largely vagally mediated, whereas hypotension was vascular in origin. These findings identify stage-specific developmental windows for cardiovascular programming and are consistent with a modular model in which peripheral effector mechanisms may be reprogramed independently of central baroreflex pathways.