TY - JOUR
T1 - Sex-biased TGFβ signalling in pulmonary arterial hypertension
AU - Wits, Marius
AU - Becher, Clarissa
AU - de Man, Frances
AU - Sanchez-Duffhues, Gonzalo
AU - Goumans, Marie-José
N1 - Funding Information: Our research is supported by the Dutch Cardiovascular Alliance (Hartstichting, Nederlandse Federatie van Universitair Medische Centra (NFU), Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Koninklijke Nederlandse Akademie van Wetenschappen), PHAEDRA-IMPACT (CVON-2018-29) and DOLPHIN-GENESIS (CVON-2017-10). GSD is also sponsored by Fundació La Marato de TV3 (grant #202038), the Spanish Ministerio de Ciencia e Innovación (“Ramon y Cajal” grant RYC2021-030866-I and PID2022-141212OA-I00). GSD and FdM are supported by the BHF-DZHK-DHF, 2022/23 award PROMETHEUS. Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex differences in PAH are evident, which primarily presents with a female predominance and increased male severity. Disturbed signalling of the transforming growth factor-β (TGFβ) family and gene mutations in the bone morphogenetic protein receptor 2 (BMPR2) are risk factors for PAH development, but how sex-specific cues affect the TGFβ family signalling in PAH remains poorly understood. In this review, we aim to explore the sex bias in PAH by examining sex differences in the TGFβ signalling family through mechanistical and translational evidence. Sex hormones including oestrogens, progestogens, and androgens, can determine the expression of receptors (including BMPR2), ligands, and soluble antagonists within the TGFβ family in a tissue-specific manner. Furthermore, sex-related genetic processes, i.e. Y-chromosome expression and X-chromosome inactivation, can influence the TGFβ signalling family at multiple levels. Given the clinical and mechanistical similarities, we expect that the conclusions arising from this review may apply also to hereditary haemorrhagic telangiectasia (HHT), a rare vascular disorder affecting the TGFβ signalling family pathway. In summary, we anticipate that investigating the TGFβ signalling family in a sex-specific manner will contribute to further understand the underlying processes leading to PAH and likely HHT.
AB - Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex differences in PAH are evident, which primarily presents with a female predominance and increased male severity. Disturbed signalling of the transforming growth factor-β (TGFβ) family and gene mutations in the bone morphogenetic protein receptor 2 (BMPR2) are risk factors for PAH development, but how sex-specific cues affect the TGFβ family signalling in PAH remains poorly understood. In this review, we aim to explore the sex bias in PAH by examining sex differences in the TGFβ signalling family through mechanistical and translational evidence. Sex hormones including oestrogens, progestogens, and androgens, can determine the expression of receptors (including BMPR2), ligands, and soluble antagonists within the TGFβ family in a tissue-specific manner. Furthermore, sex-related genetic processes, i.e. Y-chromosome expression and X-chromosome inactivation, can influence the TGFβ signalling family at multiple levels. Given the clinical and mechanistical similarities, we expect that the conclusions arising from this review may apply also to hereditary haemorrhagic telangiectasia (HHT), a rare vascular disorder affecting the TGFβ signalling family pathway. In summary, we anticipate that investigating the TGFβ signalling family in a sex-specific manner will contribute to further understand the underlying processes leading to PAH and likely HHT.
KW - Activin
KW - Androgen
KW - BMP
KW - BMPR2
KW - Endothelial
KW - HHT
KW - Hypertension
KW - Oestrogen
KW - PAH
KW - TGFβ
UR - http://www.scopus.com/inward/record.url?scp=85176754007&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/cvr/cvad129
DO - https://doi.org/10.1093/cvr/cvad129
M3 - Review article
C2 - 37595264
SN - 0008-6363
VL - 119
SP - 2262
EP - 2277
JO - Cardiovascular research
JF - Cardiovascular research
IS - 13
ER -