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The Role of Sex in the Pathophysiology of Pulmonary Hypertension

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Sex-Specific Analysis of Cardiovascular Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1065))

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by increased pulmonary vascular resistance and pulmonary artery remodelling as result of increased vascular tone and vascular cell proliferation, respectively. Eventually, this leads to right heart failure. Heritable PAH is caused by a mutation in the bone morphogenetic protein receptor-II (BMPR-II). Female susceptibility to PAH has been known for some time, and most recent figures show a female-to-male ratio of 4:1. Variations in the female sex hormone estrogen and estrogen metabolism modify FPAH risk, and penetrance of the disease in BMPR-II mutation carriers is increased in females. Several lines of evidence point towards estrogen being pathogenic in the pulmonary circulation, and thus increasing the risk of females developing PAH. Recent studies have also suggested that estrogen metabolism may be crucial in the development and progression of PAH with studies indicating that downstream metabolites such as 16α-hydroxyestrone are upregulated in several forms of experimental pulmonary hypertension (PH) and can cause pulmonary artery smooth muscle cell proliferation and subsequent vascular remodelling. Conversely, other estrogen metabolites such as 2-methoxyestradiol have been shown to be protective in the context of PAH. Estrogen may also upregulate the signalling pathways of other key mediators of PAH such as serotonin.

Right heart failure in a PAH patient. Artwork by Piet Michiels, Leuven, Belgium

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  1. Research Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

    Craig K. Docherty, Katie Yates Harvey, Kirsty M. Mair, Sinead Griffin, Nina Denver & Margaret R. MacLean

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  1. Department of Radiology and Nuclear Medicine, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands

    Peter L. M. Kerkhof

  2. Mayo Clinic, Rochester, Minnesota, USA

    Virginia M. Miller

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Docherty, C.K., Harvey, K.Y., Mair, K.M., Griffin, S., Denver, N., MacLean, M.R. (2018). The Role of Sex in the Pathophysiology of Pulmonary Hypertension. In: Kerkhof, P., Miller, V. (eds) Sex-Specific Analysis of Cardiovascular Function. Advances in Experimental Medicine and Biology, vol 1065. Springer, Cham. https://doi.org/10.1007/978-3-319-77932-4_31

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