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

作者：Upton Paul D^*; Morrell Nicholas W

来源：Experimental Physiology, 2013, 98(8): 1262-1266.

DOI：10.1113/expphysiol.2012.069104

Germ-line mutations in the bone morphogenetic protein type II receptor (BMPR2; BMPR-II) gene, a transforming growth factor- (TGF) 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 TGFs (TGF1-3) activate the Smad2/3 pathway via the ALK5 receptor. Dysregulated TGF(1) signalling is pathogenic in fibrotic diseases. We compared two rat PH models, monocrotaline-induced PAH (MCT-PAH) and chronic normobaric hypoxia (fractional inspired O-2 10%), to address whether BMPR-II loss is common to PH and permits pathogenic TGF(1) signalling. Both models exhibited reduced lung BMPR-II expression, but increased TGF(1) 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 TGF(1) 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 TGF(1) in vascular remodelling in MCT-PAH, potentially via direct inhibition of BMP signalling.

• 出版日期2013-8