Targeting Soluble TGF-β Factors: Advances in Precision Therapy for Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a rare progressive disease characterized by pulmonary artery vascular remodeling, increased vascular resistance, and subsequent right ventricular hypertrophy and right heart failure. It is triggered by disrupted transforming growth factor (TGF)-β signaling, including loss-of-function mutations in the bone morphogenetic protein (BMP) receptor 2. Emerging treatments aim to inhibit elevated TGF-β levels or enhance diminished endothelial BMP signaling. This review aims to summarize the role of the TGF-β superfamily in the pathobiology of PAH and recent discoveries highlighting altered expression of TGF-β-related soluble factors in PAH patients that can serve as potential biomarkers and drug targets. The discussion focuses on how these altered factors can guide treatment decisions and monitor therapeutic responses, facilitating personalized patient care through the integration of diagnostics and therapy, that is, precision medicine. This approach tailors treatment strategies to individual patients based on their unique disease characteristics.

Keywords: BMPRII; endothelial; miRNAs; small extracellular vesicles; smooth muscle cell.

Graphical abstract

Central Illustration

Biomarker-Based Therapeutics in PAH Targeting TGF-β Signaling Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and a dysfunctional BMPR-II-mediated signaling as well as an overactive TGF-β pathway. Altered factors related to the TGF-β superfamily are used as biomarkers and have the potential to be utilized for precision medicine to guide therapeutic approaches and treatment decisions for PAH patients.

Figure 1

TGF-β Superfamily Signal Transduction TGF-β superfamily signal transduction. Schematic overview of the TGF-β signaling pathway. TGF-β family proteins are synthesized as precursor peptides. Through proteolytic cleavage, the latent TGF-β complex is formed consisting of the latency-associated peptide (LAP) and the mature TGF-β peptide which can form disulfide bonds with the latent TGF-β binding protein (LTBP). Binding of the active TGF-β ligands to specific TGF-β type I and II receptors in the cell membrane activates the intracellular signaling cascade. (Left) TGF-β ligands (TGF-β_1-3, inhibins and activins) bind to receptor complexes consisting of a type I (ALK4/5/7) and type II (TGFBRII, ACVRIIA/B) receptor. The binding of the ligands to its receptor complexes leads to phosphorylation and activation of SMAD2/3. (Right) BMP ligands (BMP2/4/5/6/7/9/10) generally bind to receptor complexes of ALK1/ALK2/ALK3/ALK6 (type I receptor) and ACVRIIA/ACVRIIB/BMPRII (type II receptor) resulting in phosphorylation of SMAD1/5/8. These SMADs interact with SMAD4 and induce the transcription of specific target genes. Co-receptors (endoglin/TGFBRIII) can fine tune receptor-ligand affinity. Soluble antagonists (Follistatin/Chordin/Noggin/Gremlin-1) can function as ligand traps to decrease their availability. Several genes encoding TGF-β factors have been described to be mutated in PAH (encircled in red) leading generally to a decreased BMP and (in)direct increased TGF-β signaling. Inhibitory SMADs (I-SMADs 6 and 7) interact with Smurf 1 and 2 and regulate TGF-β signaling by blocking activation of R-SMADs and induction of receptor degradation. ACVRII = activin receptor type II; ALK = activin receptor like kinase; BMP = bone morphogenic protein; BMPRII = bone morphogenic protein receptor type 2; CAV-1 = caveolin-1; ENG = endoglin; SMAD = small mothers against decapentaplegic; TGF-β = transforming growth factor beta; TGFBRII/III = transforming growth factor beta receptor type II/III.

Figure 2

Therapeutic Approaches to Target Altered TGFβ Signaling Altered TGFβ related factors in PAH and therapeutic approaches to target the TGFβ superfamily. (A) Members of the TGFβ superfamily altered in PAH comprise ligands (BMP9, BMP10, TGFβ, activin (A) Soluble antagonists (Follistatin, Gremlin-1) and membrane-bound receptors (BMPRII). Most of those factors are increased (encircled in red) in the context of PAH, others are reported to be decreased (encircled in green) in PAH patients. (B) Therapeutic approaches to target the TGFβ superfamily comprise: 1) adenoviral-mediated delivery of BMPRII or Follistatin, inhibition of TGFβ/Activin signaling; with 2) ACVRIIA/B and TGFBRII-Fc fusion proteins; 3) neutralizing antibodies; 4) ALK-5 inhibition with small molecules; 5) antisense oligonucleotides blocking the production of TGFβ₂, or enhancement of BMP signaling; by 6) recombinant BMP9; 7) inhibition of soluble antagonists with Gremlin-1 neutralizing antibodies; 8) FKBP12 inhibition; and 9) restoration of BMPRII surface trafficking by e.g., inhibiting lysosomal degradation (Hydroxychloroquine) or the release of trapped BMPRII in the endoplasmic reticulum (ER) (Sodium 4-PBA). Created with BioRender.com. ACVRII = activin receptor type II; ALK = activin receptor like kinase; BMP = bone morphogenic protein; BMPRII = bone morphogenic protein receptor type 2; FKBP-12 = FK-binding protein 12; SMAD = small mothers against decapentaplegic; sodium 4- PBA = sodium 4-phenylbutyrate; TGFβ = transforming growth factor beta; TGFBRII/III = transforming growth factor beta receptor type II/III.