Fetal origins of cardiovascular dysfunction in an ovine model of maternal obesity in pregnancy

Obesity prevalence has reached epidemic proportions worldwide, including in women of reproductive age. Studies in humans and animal models have shown that exposure to obesity during pregnancy increases the cardiometabolic disease risk in the offspring, independent of genetic and postnatal environmental factors. However, whether cardiometabolic dysfunction in the offspring originates in fetal life remains under-investigated. To address this knowledge gap, we generated a novel ovine model of maternal diet-induced obesity during pregnancy to investigate its impacts on fetal cardiovascular physiology. We adopted an integrative approach, combining experiments of fetal cardiovascular function in vivo following surgical instrumentation with investigation at the isolated organ, cellular and molecular levels. Maternal obesity, as expected, was characterised by increased body weight and adiposity, metabolic dysfunction and hypertension in the mother. Fetuses of obese pregnancy showed circulatory brain sparing with increased carotid oxygen delivery at baseline, mediated by enhanced cerebral artery dilator reactivity and increased nitric oxide bioavailability. Fetuses of obese pregnancy also had improved brain-sparing defences to acute hypotensive and acute hypoxic challenges, driven by peripheral vascular sympathetic hyper-reactivity and enhanced nitric oxide signalling. While fetal cardiac parasympathetic influences were enhanced, fetal cardiac sympathetic influences were blunted in obese pregnancy, revealed through alterations in basal heart rate variability and cardiac baroreflex function. In addition, biventricular systolic and diastolic dysfunction was observed at baseline. Fetuses of obese pregnancy were protected from exposure to ischaemia during a maternal acute hypotensive challenge through improved maintenance of maternal uterine blood flow. Combined, these data reveal alterations in fetal cardiovascular function in obese pregnancy which improve the fetal defence to common acute challenges in utero. Underlying mechanisms include enhanced nitric oxide signalling and sympathetic hyper-reactivity, which may have occurred secondary to hyperinsulinaemia and increased vascular insulin sensitivity in fetuses of obese pregnancy. Persistence into postnatal life of sympathetic hyper-reactivity, and the development of endothelial dysfunction secondary to vascular insulin resistance, may switch this transient fetal advantage to longer-term disadvantage. These finding suggest a potential pathway for programmed cardiovascular dysfunction in the adult offspring via mechanisms that originated in fetal life.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Cochrane, Anna

Advisors dc:contributor.advisor

• Giussani, Dino
• Ozanne, Susan

• Cardiovascular
• Fetal physiology
• Maternal obesity

Licence

• https://www.repository.cam.ac.uk/bitstreams/0d76a04b-34b7-4c11-a535-67eb7280086b/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.125192

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/395795