Sex-biased TGFβ signalling 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 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.

Keywords: Activin; Androgen; BMP; BMPR2; Endothelial; HHT; Hypertension; Oestrogen; PAH; TGFβ.

Graphical Abstract

Figure 1

Schematic representation of the TGFβ signalling family. Ligands of the TGFβ family (TGFβ1–3, Activin A, BMP2/4/5/6/7/9/10, AMH) bind their type I (ALK1/2/3/4/5/6) and II (TGFβR2, ACTR2A/B, BMPR2, AMHR2) plasma membrane receptors. Soluble antagonists (Follistatin, Chordin, Noggin, Gremlin) can decrease ligand accessibility. Type III receptors (i.e., endoglin) can further regulate ligand–receptor complex formation. Upon Type I receptor activation, the intracellular signalling molecules (R-SMADs) are phosphorylated and form a heterotrimeric complex with SMAD4. ALK4/5 (stimulated by TGFβ/Activin A ligands) signal via SMAD2/3 whereas ALK1/2/3/6 (stimulated by BMP/AMH ligands) signal via SMAD1/5/8. R-SMAD/SMAD4 complexes translocate to the nucleus to regulate the activity of gene promoters. Also non-canonical signalling (JNK, ERK, p38, PI3K/Akt) can occur via TGFβ signalling. Mutations in genes encoding TGFβ factors have been linked to PAH development. Not all factors within the TGFβ signalling family have been incorporated in the figure for clarity purposes. PAH, pulmonary arterial hypertension; TGFβ, transforming growth factor-β; BMP, bone morphogenetic protein; AMH, anti-Müllerian hormone; CAV-1, caveolin-1; ENG, endoglin; ALK, activin receptor-like kinase; TGFβR2, TGFβ receptor 2; ACTR2, activin receptor Type II; BMPR2, BMP receptor Type II; SMAD, small mothers against decapentaplegic; JNK, c-jun N-terminal kinase; ERK, extracellular signal-regulated kinase; PI3K, phosphoinositide 3-kinase; SRE, SMAD responsive element.

Figure 2

A schematic depiction of the splice variants (A) and signalling function (B) of endoglin on TGFβ1 signalling. The short (S-) and long (L-)endoglin variants are alternatively spliced by excluding or including exon 14, respectively (A). Both S- and L-endoglin increases TGFβ1 signalling; however, S-endoglin favours ALK5 signalling where L-endoglin favours ALK1 dependent signalling (B). Therefore, as observed by,^, a balance shift towards S-endoglin increases TGFβ signalling by SMAD2/3 phosphorylation. TGF, transforming growth factor; ALK, activin-like kinase; SMAD, small mothers against decapentaplegic.

Figure 3

Sotatercept (ACTR2A-Fc) sequesters TGFβ ligands to restore the disbalanced signalling in PAH. The soluble ligands activin A, GDF8/11 and TGFβ1/3 are elevated in PAH causing increased SMAD2/3 phosphorylation over SMAD1/5/8 signalling. This disturbed TGFβ signalling underlies increased pulmonary arterial thickening with a subsequent rise in pulmonary arterial pressure and right ventricle hypertrophy. Treatment with Sotatercept normalizes the signalling imbalance by shielding soluble TGFβ ligands, resulting in a decrease in pulmonary arterial thickening and right ventricle hypertrophy. *Low affinity inhibition of BMP10 by Sotatercept might disturb endothelial homeostasis and subsequently causing telangiectasias. TGF, transforming growth factor; GDF, growth differentiation factor; BMP, bone morphogenetic protein; ALK, activin receptor-like kinase; ACTR2, activin receptor Type II; BMPR2, BMP receptor Type II; SMAD, small mothers against decapentaplegic.

Figure 4

Signalling crosstalk of sex hormones and TGFβ signalling. The membrane permeable sex hormones androgens, progestogens, and oestrogens bind their nuclear receptors androgen receptor (AR), progestogen receptor (PR), and oestrogen receptor (ER), respectively. Oestrogens also bind the membrane receptor G-protein-coupled oestrogen receptor (GPER). Sex-hormones crosstalk on three different levels with TGFβ signalling. (1) The activated nuclear receptors can directly interact with SMADs to inhibit downstream signalling. Oestrogen-ER signalling has been associated with SMURF1-mediated proteasomal degradation of SMADs. (2) All sex-hormones have shown to regulate TGFβ target genes, via their corresponding responsive elements. (3) The oestrogen-GPER signalling cascade includes routes overlapping non-canonical TGFβ signalling routes. TGFβ, transforming growth factor-β; BMP, bone morphogenetic protein; AMH, anti-Müllerian hormone; AR/PR/ER, androgen/progestogen/oestrogen receptor; GPER, G-protein-coupled oestrogen receptor; SRE/ARE/PRE/ERE, SMAD/androgen/progestogen/oestrogen responsive element; SMAD, small mothers against decapentaplegic; SMURF, SMAD specific ubiquitin ligase.

Figure 5

Genetics sex-related differences on the TGFβ signalling family in health and PAH. (A) In females, proper X-chromosome inactivation results in healthy genetic output leading to a balanced TGFβ/BMP signalling. However, disturbances in X-chromosome inactivation results in dysregulated genes (escapees) and increased genetic output which might cause a diseased disbalance in TGFβ/BMP signalling. (B) In males, SRY has been linked to increased BMPR2 expression, while USP9Y is an ubiquitin-dependent hydrolase that targets SMAD4. TGFβ, transforming growth factor-β, BMP, bone morphogenetic protein; SMAD, small mothers against decapentaplegic; SRY, sex-determining region of Y; USP9Y, ubiquitin specific peptidase 9 Y-linked; BMPR2, BMP receptor Type 2.