There are many approaches we can take in our effort to understand the pathophysiology of pulmonary arterial hypertension (PAH); in this article, we will examine PAH primarily as a connective tissue disease that is associated with systemic sclerosis. 

Xu and colleagues, in their study exploring the role of microRNA (miRNA) in PAH and systemic sclerosis, wrote about the role of transforming growth factor beta (TGF-β) and bone morphogenetic protein receptor type 2 (BMPR2) signaling pathways in PAH and systemic sclerosis. These 2 pathways have long been implicated in PAH pathophysiology. 

“Systemic sclerosis is a complex, multisystem disease characterized by fibrosis and excessive collagen deposition within the skin and internal organs, chronic inflammation, autoimmune dysregulation, and microvascular endothelial dysfunction,” Xu et al wrote. In this definition, it is easy to see how PAH fits into this category of disease, given the pathological remodeling of the pulmonary vasculature associated with it. 

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In this context, PAH is the leading cause of death in systemic sclerosis; it has a dismal 50% mortality rate within 3 years of diagnosis and affects up to 12% of patients with systemic sclerosis. 

Read more about PAH etiology 

Where do TGF-β and BMPR2 come into the picture? Xu et al explained, “When mutated, BMPR2 is associated with an increased susceptibility to develop PAH,” and “dysregulated TGF-β signaling potentially causes inflammation, autoimmune disorders, fibrosis, cancer, or PAH.”

A Strong Connection

TGF-β signaling is responsible for several important processes, including angiogenesis and cellular proliferation. Studies have shown TGF-β is elevated in PAH, and scientists have “strongly implicated it in the pathogenesis of PAH,” according to Xu and colleagues. 

A study using rat models further elucidates the role of TGF-β in PAH. To induce PAH-like conditions in rat models, they were treated with monocrotaline (MCT). Researchers discovered that by inhibiting the TGF-β pathway in these rats, pulmonary hypertension was reduced.

“These findings,” Xu et al wrote, “confirmed that endothelial apoptosis induces pulmonary artery smooth muscle cell (PASMC) growth via TGF-β.” 

A Revealing Association 

Like TGF-β, BMPR2 regulates many important processes, such as embryogenesis and development, as well as adult tissue homeostasis. As with TGF-β, studies have demonstrated how BMPR2 and PAH are linked. “A previous study revealed reduced BMPR2 protein in patients with systemic sclerosis-PAH, and an increased proteasomal degradation of BMPR2 was found in a relevant mouse model,” Xu et al wrote. 

And the significance? “Collectively, these results suggest that TGF-β might impair the BMP signaling through the degradation of its receptor and promote the PAH susceptibility in systemic sclerosis, which might provide a unifying mechanism across different forms of PAH,” Xu and colleagues wrote. 

The association between TGF-β and BMP signaling is indeed revealing: it shows just how interconnected signaling pathways are and how they can collectively contribute to the pathophysiology of a disease when something goes wrong. 

On BMPR2 specifically, a study has shown that it has reduced expression and downstream signaling in the lung vasculature of patients with idiopathic and hereditary PAH. This is because a deficiency in BMPR2 can increase endothelial inflammatory responses and contribute to adverse vascular remodeling. 

Clinical Significance 

Now we come to the most important part of this article: how do all these discoveries change the way we treat PAH patients? Sommer and colleagues, in their study on the current and future treatments of PAH, have a few suggestions. 

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In this article, we demonstrated that an imbalance in TGF-β/BMP signaling is an important pathogenic mechanism in PAH. “Thus, inhibition or activation of the respective receptor pathway may represent a promising strategy to treat PAH, although balancing the response might be challenging due to overlapping ligand and receptor functions,” Sommer and colleagues wrote. 

With regards to reduced BMPR2 expression in PAH, a straightforward approach would be to activate BMPR2 signaling by using BMPR2 receptor agonists. In this regard, tacrolimus is a promising drug candidate. Sommer et al explained, “Tacrolimus prevented the development of PAH in mice with endothelial deletion of BMPR2 and reversed established PAH in two rat models.” 

Upon reflection of their work in elucidating the role of TGF-β/BMPR2 signaling pathways, Xu and colleagues wrote, “In some ways, the complexity of the hierarchical motifs governing their multifunctional and interconnected activities has brought more confusion to the precise, organized structure of miRNA-based mechanisms that drive disease.” 

In other words, the more we dig, the more we realize how much further we have to go. In view of the ever-broadening medical literature around PAH pathophysiology, what angles can future researchers pursue? Xu et al wrote that “the next phase of research and discovery will necessitate a pipeline of systematic endeavors designed to catalog and identify the hierarchy of activity inherent in these molecular networks.” 

The payoff of such endeavors, if conducted persistently and diligently, will be immense.

“If successful, that next level of insight should further invigorate interest from academia, federal, and industry partners to pursue the collaborative development of more effective miRNA-based diagnostics and therapeutics based on such systems-level understanding of this disease,” Xu and colleagues wrote. 


Xu B, Xu G, Yu Y, et al. The role of TGF-β or BMPR2 signaling pathway-related miRNA in pulmonary arterial hypertension and systemic sclerosisArthritis Res Ther. Published online November 25, 2021. doi:10.1186/s13075-021-02678-6

Sommer N, Ghofrani HA, Pak O, et al. Current and future treatments of pulmonary arterial hypertensionBr J Pharmacol. 2021;178(1):6-30. doi:10.1111/bph.15016