Germ-line mutations in the bone morphogenetic protein type II receptor (BMPR-II) gene cause the majority of heritable pulmonary arterial hypertension (PAH) cases. PAH is a subset of the spectrum of pulmonary hypertension (PH) disorders, including hypoxia-related lung diseases. BMPR-II belongs to the Transforming Growth Factor beta (TGFβ) receptor superfamily. Bone morphogenetic proteins (BMPs), via BMPR-II, activate the canonical Smad1/5/9 pathway to induce target genes, such as ID1-4. TGFβs (TGFβ1-3), signalling via the ALK5 receptor, regulate various cellular processes through the canonical Smad2/3 pathway. Dysregulated TGFβ1 signalling is pathogenic in fibrotic kidney and lung diseases. Our studies have addressed whether BMPR-II loss is a common feature of PH and if it correlates to enhanced TGFβ1 signalling in PH. This question has been addressed via studies of interaction between the BMP and TGFβ pathways in animal PH models and human pulmonary artery smooth muscle cells (PASMCs). PH can be induced in rats by injecting the plant alkaloid, monocrotaline, resulting in progressive disease (MCT-PAH), or exposure to chronic normobaric hypoxia (FiO2 10% O2). In our studies, both hypoxic PH and MCT-PAH were associated with reduced lung BMPR-II protein and mRNA (1). However, significant increases in TGFβ1 and decreased Smad/ID responses were only observed in MCT-PAH(1). To investigate the role of TGFβ1 further, we administered a pharmacological inhibitor of the TGFβ type I receptor, ALK5. This inhibitor prevented disease progression in the MCT-PAH model, but not in hypoxia (1). In vitro studies have also been performed using PASMCs from donor lungs and BMPR-II mutation positive PAH PASMCs. The mutation-bearing PASMCs exhibit reduced BMP4 responsiveness(2). TGFβ1 attenuated BMP4-mediated ID1/2 induction and activation of a Smad-dependent luciferase reporter, yet did not alter Smad phosphorylation. Conversely, BMP4 did not alter TGFβ1-mediated responses. The inhibitory effect of TGFβ1 upon BMP4 responses was reversed by ALK5 inhibition and by Smad3 siRNA, but was unaffected by Smad2 siRNA. In conclusion, our studies have shown that BMPR-II loss is common to the hypoxic and MCT PH models, but systemic ALK5 inhibition is only effective in the MCT model, highlighting a specific role for TGFβ1 in vascular remodelling in MCT-PAH. On the background of reduced BMPR-II, TGFβ1 exerts a potential pathogenic role via inhibition of the BMP-Smad transcriptional pathway through a Smad3-dependent mechanism. Therefore, intravenous anti-TGFβ1 therapy may be more effective in PAH, particularly related to BMPR-II mutations, rather than hypoxic PH.