The transforming growth factor-β-bone morphogenetic protein type signalling pathway in pulmonary vascular homeostasis and disease

摘要

New Findings: ? What is the Topic of this review? This review summarises our current knowledge of dysregulated bone morphogenetic protein (BMP) and transforming growth factor-β1 (TGFβ1) signalling in pulmonary arterial hypertension. ? What advances does it highlight? Reduced expression of the bone morphogenetic protein (BMP) type II receptor is common to the monocrotaline (MCT-PAH) and hypoxic rat models of pulmonary hypertension (PH). However, reduced BMP signalling and enhanced transforming growth factor-β1 (TGFβ1) signalling is observed only in MCT-PAH. Furthermore, TGFβ1 receptor blockade blocks MCT-PAH, but not hypoxic PH. Transforming growth factor-β1 inhibits BMP signalling in pulmonary artery smooth muscle cells. Germ-line mutations in the bone morphogenetic protein type II receptor (BMPR2; BMPR-II) gene, a transforming growth factor-β (TGFβ) receptor superfamily member, cause the majority of cases of heritable pulmonary arterial hypertension (PAH). Pulmonary arterial hypertension is a subset of pulmonary hypertension (PH) disorders, which also encompass hypoxia-related lung diseases. Bone morphogenetic proteins (BMPs), via BMPR-II, activate the canonical Smad1/5/9 pathway, whereas TGFβs (TGFβ1-3) activate the Smad2/3 pathway via the ALK5 receptor. Dysregulated TGFβ1 signalling is pathogenic in fibrotic diseases. We compared two rat PH models, monocrotaline-induced PAH (MCT-PAH) and chronic normobaric hypoxia (fractional inspired O2 10%), to address whether BMPR-II loss is common to PH and permits pathogenic TGFβ1 signalling. Both models exhibited reduced lung BMPR-II expression, but increased TGFβ1 signalling and decreased BMP signalling were observed only in MCT-PAH. Furthermore, a pharmacological ALK5 inhibitor prevented disease progression in the MCT-PAH model, but not in hypoxia. In vitro studies using human pulmonary artery smooth muscle cells showed that TGFβ1 directly inhibits BMP-Smad signalling. In conclusion, BMPR-II loss is common to the hypoxic and MCT-PAH models, but systemic ALK5 inhibition is effective only in the MCT model, highlighting a specific role for TGFβ1 in vascular remodelling in MCT-PAH, potentially via direct inhibition of BMP signalling.