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The transforming growth factor‐β–bone morphogenetic protein type signalling pathway in pulmonary vascular homeostasis and disease
Author(s) -
Upton Paul D.,
Morrell Nicholas W.
Publication year - 2013
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/expphysiol.2012.069104
Subject(s) - bmpr2 , smad , bone morphogenetic protein , transforming growth factor , pulmonary hypertension , bone morphogenetic protein receptor , vascular remodelling in the embryo , hypoxia (environmental) , endocrinology , biology , medicine , lung , cancer research , receptor , bone morphogenetic protein 2 , chemistry , in vitro , biochemistry , gene , organic chemistry , oxygen
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‐β 1 (TGFβ 1 ) 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‐β 1 (TGFβ 1 ) signalling is observed only in MCT‐PAH. Furthermore, TGFβ 1 receptor blockade blocks MCT‐PAH, but not hypoxic PH. Transforming growth factor‐β 1 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 TGFβ 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 TGFβ 1 signalling. Both models exhibited reduced lung BMPR‐II expression, but increased TGFβ 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 TGFβ 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 TGFβ 1 in vascular remodelling in MCT‐PAH, potentially via direct inhibition of BMP signalling.