Sarah Al Nemri

Background: Pulmonary hypertension (PH) affects over 50-70 million people worldwide, with an average survival rate of 54% at 5 years with current therapies.1 BMPR2 mutation accounts for 70-80% of heritable PAH cases and 10-40% of idiopathic pulmonary arterial hypertension (PAH) cases. Novel therapies in clinical trials target BMPR2 and have been shown to safely reverse disease progression and decrease pulmonary vascular resistance.2

Objective: This review summarizes current literature on BMPR2 modulation as a therapeutic target for pulmonary hypertension, exploring clinical and emerging strategies for its regulation and application.

Search Methods: Primary research articles using the search terms “BMPR2 pulmonary hypertension” conducted over the past 5 years (2025-2020) were found through PubMed and included.

Results: Epidemiological studies have found that BMPR2 mutations are associated with higher pulmonary arterial pressure, earlier age of diagnosis, worse prognosis, increased risk of death or transplantation, and higher all-cause mortality. The familial mutation is inherited in an autosomal dominant pattern with a greater prevalence and penetrance in females compared to males.3Switch-i  ndependent 3A (SIN3A) is  an epigenetic modifier strongly associated with BMPR2 expression. Silencing leads to cyclin D1 overexpression, contributing to disordered proliferation of human pulmonary artery smooth muscle cells (hPASMC). On the other hand, endotracheal delivery of SIN3A using adeno-associated virus in rodent models resulted in a decrease in right ventricle systolic pressure and mean pulmonary arterial pressure. Overexpression of SIN3A showed a decrease in methylation of the BMPR2 promoter region exclusively in hPASMCs.4Transcription co-activator   MED1 and transcription factor KLF4 are decreased in the lung endothelium of idiopathic PAH patients and rodent PH models. These two factors function together to transactive BMPR2 and TGF-βR2 via chromatin remodeling, playing important roles in the homeostatic function of receptor signaling. Studies in mice with endothelial-specific MED1 deletion revealed aggravated PH and impaired acetylcholine-induced vasodilation. Variations in TGF-βR2 expression can influence the severity of PH by modulating angiogenesis. This occurs through opposing pathways: ALK5-Smad2/3 signaling inhibits angiogenesis, while ALK1-Smad1/5 signaling promotes it.5  Caspase-3/gasdermin E mediated endothelial cell pyroptosis is associated with Cathepsin L, a cysteine protease found to be elevated in the pulmonary artery endothelium of idiopathic PAH patients. Genetic ablation of cathepsin L relieves pulmonary vascular remodeling, right ventricular systolic pressure, and right ventricular hypertrophy and restores endothelial function.6  Sotatercept is a novel drug therapy that binds activin-growth differentiation factors associated with BMP pathway signaling. When used with background therapy over 24 weeks, a 0.3-0.7 mg/kg dosage significantly decreased pulmonary vascular resistance in PAH patients. Thrombocytopenia was the primary adverse effect found, but was reversible after delay, reduction, or discontinuation.2

Conclusion: Collectively, these findings illustrate how multiple failures in the BMPR2/TGF-β axis (genetic mutations, epigenetic suppression, inflammatory degradation) converge to drive PH, and how repairing this axis can ameliorate disease.2 Therapeutic strategies that restore BMPR2 signaling (such as Sotatercept) target the underlying molecular abnormalities in PAH, offering the potential for more effective disease treatment beyond symptomatic management.2

Works Cited

1. Corris PA, Seeger W. Call it by the correct name—pulmonary hypertension not pulmonary arterial hypertension: Growing recognition of the global health impact for a well-recognized condition and the role of the Pulmonary Vascular Research Institute. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2020;318(5). doi:10.1152/ajplung.00098.2020
2. Humbert M, McLaughlin V, Gibbs JS, et al. Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med.2021;384(13):1204-1215. doi:10.1056/NEJMoa2024277.
3. Montani D, Girerd B, Jaïs X, Laveneziana P, Lau EMT, Bouchachi A, Hascoët S, Günther S, Godinas L, Parent F, Guignabert C, Beurnier A, Chemla D, Hervé P, Eyries M, Soubrier F, Simonneau G, Sitbon O, Savale L, Humbert M. Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation. Eur Respir J. 2021 Jul 22;58(1):2004229. doi: 10.1183/13993003.04229-2020. PMID: 33380512; PMCID: PMC8295506.
4. Bisserier M, Mathiyalagan P, Zhang S, et al. Regulation of the Methylation and Expression Levels of the BMPR2 Gene by SIN3a as a Novel Therapeutic Mechanism in Pulmonary Arterial Hypertension. Circulation. 2021;144(1):52-73. doi:10.1161/CIRCULATIONAHA.120.047978
5. Wang C, Xing Y, Zhang J, et al. MED1 Regulates BMP/TGF-β in Endothelium: Implication for Pulmonary Hypertension. Circ Res. 2022;131(10):828-841. doi:10.1161/CIRCRESAHA.122.321532
6. Wang C, Xing Y, Zhang J, et al. MED1 Regulates BMP/TGF-β in Endothelium: Implication for Pulmonary Hypertension. Circ Res. 2022;131(10):828-841. doi:10.1161/CIRCRESAHA.122.321532