TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

Abstract

Knowledge pertaining to the involvement of transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling in pulmonary arterial hypertension (PAH) is continuously increasing. There is a growing understanding of the function of individual components involved in the pathway, but a clear synthesis of how these interact in PAH is currently lacking. Most of the focus has been on signaling downstream of BMPR2, but it is imperative to include the role of TGF-β signaling in PAH. This review gives a state of the art overview of disturbed signaling through the receptors of the TGF-β family with respect to vascular remodeling and cardiac effects as observed in PAH. Recent (pre)-clinical studies in which these two pathways were targeted will be discussed with an extended view on cardiovascular research fields outside of PAH, indicating novel future perspectives.

Keywords: bone morphogenetic protein; pathophysiology; pulmonary arterial hypertension; signaling; transforming growth factor β; treatment.

Figure 1

TGF-β and BMP signaling. Receptors with evidence of mutations in pulmonary arterial hypertension (PAH) are underlined [17]. Abbreviations: ActRII, activin receptor type II; ALK, activing receptor-like kinase; BMP, bone morphogenetic protein; GDF, growth/differentiation factor; TGF, transforming growth factor.

Figure 2

Proposed mechanism of TGF-β signaling in the pathogenesis of pulmonary arterial hypertension. Abbreviations: ActRII, Activin receptor type II; AKT, protein kinase B; ALK1, activin receptor-like kinase 1; CTGF, connective tissue growth factor; ERK, extracellular signal-regulated kinases; GDF, growth/differentiation factor; JNK, c-Jun N-terminal kinases; MAPK, mitogen-activated protein kinase; PAI-1, plasminogen activator inhibitor-1; TGF-β, transforming growth factor β. TGFBRII, TGF-β receptor type II.