Sex-biased TGFβ signaling in pulmonary arterial hypertension.

Abstract

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 transduction of the transforming growth factor-β (TGFβ) signaling 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 signaling family in PAH remains poorly understood. In this review we aim to explore the sex-bias in PAH by examining sex-differences in the TGFβ signaling family through mechanistical and translational evidence. Sex-hormones including estrogens, 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 signaling family at multiple levels. Given the clinical and mechanistical similarities, we expect that the conclusions arising from this review may apply also to hereditary hemorrhagic telangiectasia (HHT), a rare vascular disorder affecting the TGFβ signaling family pathway. In summary, we anticipate that investigating the TGFβ signaling family in a sex-specific manner will contribute to further understand the underlying processes leading to PAH and likely HHT.