Maternal androgen excess induces cardiac hypertrophy and left ventricular dysfunction in female mice offspringShow others and affiliations
2020 (English)In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 116, no 3, p. 619-632Article in journal (Refereed) Published
Abstract [en]
Aims: Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is suggested to increase the risk for cardiovascular disease. How PCOS may lead to adverse cardiac outcomes is unclear and here we hypothesized that prenatal exposure to dihydrotestosterone (DHT) and/or maternal obesity in mice induce adverse metabolic and cardiac programming in female offspring that resemble the reproductive features of the syndrome.
Methods and results: The maternal obese PCOS phenotype was induced in mice by chronic high-fat–high-sucrose consumption together with prenatal DHT exposure. The prenatally androgenized (PNA) female offspring displayed cardiac hypertrophy during adulthood, an outcome that was not accompanied by aberrant metabolic profile. The expression of key genes involved in cardiac hypertrophy was up-regulated in the PNA offspring, with limited or no impact of maternal obesity. Furthermore, the activity of NADPH oxidase, a major source of reactive oxygen species in the cardiovascular system, was down-regulated in the PNA offspring heart. We next explored for early transcriptional changes in the heart of newly born PNA offspring, which could account for the long-lasting changes observed in adulthood. Neonatal PNA hearts displayed an up-regulation of transcription factors involved in cardiac hypertrophic remodelling and of the calcium-handling gene, Slc8a2. Finally, to determine the specific role of androgens in cardiovascular function, female mice were continuously exposed to DHT from pre-puberty to adulthood, with or without the antiandrogen flutamide. Continuous exposure to DHT led to adverse left ventricular remodelling, and increased vasocontractile responses, while treatment with flutamide partly alleviated these effects.
Conclusion: Taken together, our results indicate that intrauterine androgen exposure programmes long-lasting heart remodelling in female mouse offspring that is linked to left ventricular hypertrophy and highlight the potential risk of developing cardiac dysfunction in daughters of mothers with PCOS.
Place, publisher, year, edition, pages
Oxford University Press, 2020. Vol. 116, no 3, p. 619-632
National Category
Medical and Health Sciences Physiology and Anatomy
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-17854DOI: 10.1093/cvr/cvz180ISI: 000518548100020PubMedID: 31382275Scopus ID: 2-s2.0-85076000325OAI: oai:DiVA.org:his-17854DiVA, id: diva2:1368191
Funder
Swedish Heart Lung Foundation, 20170124Swedish Heart Lung Foundation, 20180568Novo Nordisk Foundation, NNF16OC0020744Novo Nordisk Foundation, NNF17OC0026724Novo Nordisk Foundation, NNF18OC0033992Karolinska InstituteRegion Stockholm
Note
This work was supported by the Swedish Medical Research Council [2014-2775 and 2018-02435 to E.S.V., 2016-01381 to M.C.]; the Swedish Heart and Lung Foundation [20170124 and 20180568 to M.C.]; the Novo Nordisk Foundation [NNF16OC0020744, NNF17OC0026724, and NNF18OC0033992 to E.S.V.]; the SRP in Diabetes at Karolinska Institutet to E.S.V.; and the Regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet to E.S.V.
2019-11-062019-11-062025-03-10Bibliographically approved