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Long-Term Adverse Effects of Perinatal Hypoxia on the Adult Pulmonary Circulation Vary Between Males and Females in a
A-C Peyter1, V Muehlethaler, J-F Tolsa
1Neonatal Res Lab, Dept Woman-Mother-Child, Lausanne Univ Hosp and Univ Lausanne, Lausanne, Switzerland. Anne-Christine.Peyter@chuv.ch.
Insights
Perinatal hypoxia causes lasting pulmonary circulation changes in adults, with males showing increased resistance and females exhibiting vascular dysfunction. Sex differences in these long-term effects are significant.
Area of Science:
- Cardiovascular Science
- Pulmonary Medicine
- Developmental Biology
Background:
- Adverse perinatal events increase later-life cardiometabolic disease risk.
- Perinatal hypoxia (PH) models long-term pulmonary circulation effects.
- Previous studies linked PH to altered vascular tone, K+ channels (males), and NO/cGMP pathways (females).
Purpose of the Study:
- To investigate long-term effects of perinatal hypoxia on adult pulmonary circulation.
- To identify sex-specific alterations in pulmonary vascular function and structure.
- To evaluate the protective role of inhaled nitric oxide (iNO) during PH.
Main Methods:
- Established a murine model of perinatal hypoxia.
- Assessed right ventricular pressure and pulmonary artery relaxation.
- Performed morphometric analysis of pulmonary vessels.
- Evaluated responses to acute hypoxia and acetylcholine-induced relaxation.
Main Results:
- PH increased right ventricular pressure and sensitivity to hypoxia in females.
- PH reduced acetylcholine-induced relaxation, more in females than males.
- PH caused right ventricular hypertrophy earlier in males.
- PH increased pulmonary vessel number in males, suggesting increased resistance.
- Perinatal iNO during PH mitigated adverse effects, but iNO alone had risks.
Conclusions:
- Perinatal hypoxia induces sex-specific, long-lasting pulmonary circulation alterations.
- Males exhibit increased pulmonary vascular resistance with morphological changes.
- Females display significant pulmonary vascular dysfunction.
- Perinatal iNO can prevent PH-induced damage, highlighting its therapeutic potential.
Abstract:
Adverse events during the perinatal period are associated with an increased risk to develop cardiometabolic diseases later in life. We established a murine model to study long-term effects of perinatal hypoxia (PH) on the pulmonary circulation. We previously demonstrated that PH led to an impaired regulation of pulmonary vascular tone in adulthood, linked to alterations in K+ channels in males and in the nitric oxide (NO)/cyclic guanosine monophosphate pathway in females. Moreover, simultaneous administration of inhaled NO (iNO) during PH exposure prevented adverse effects of PH on adult pulmonary vasculature in females. The present study showed that PH induced a significant increase in right ventricular pressure in males and females, and an enhanced sensitivity to acute hypoxia in females. PH significantly reduced acetylcholine-induced relaxation in pulmonary artery, to a greater extent in females than in males. PH led to right ventricular hypertrophy in adulthood, appearing earlier in males than in females. Morphometric measurements showed a significant increase in the number of 25-75-µm pulmonary vessels in male lungs following PH, probably resulting in increased pulmonary vascular resistance. The effects of prolonged hypoxia in adulthood differed between males and females. Perinatal iNO during PH prevented PH-induced alterations in the cardiopulmonary system, whereas perinatal iNO alone could have some adverse effects. Therefore, PH led to long-lasting alterations in the regulation of adult pulmonary circulation, which vary between males and females. In males, the increased pulmonary vascular resistance was associated with morphological changes besides functional alterations, whereas females showed an important pulmonary vascular dysfunction. Keywords: Perinatal hypoxia, Pulmonary circulation, Endothelium-dependent relaxation, Phosphodiesterases, Sex differences.
