Figure 2.

Proposed mechanism for the restoration of cell surface BMPR-II expression and signalling using exogenous BMP9 therapy. Left panel: Under normal conditions an individual possesses two wild-type alleles for BMPR2. Under these circumstances BMP9 signalling involves signalling via the ALK1:BMPR-II ligand receptor complex and activation of the Smad1/4 transcriptional complex.¹ This promotes BMPR-II mRNA transcription and synthesis² and trafficking of newly-synthesised BMPR-II to the cell surface where it complexes with ALK1, which has been recycled via the endosomal pathway.³ In the presence of BMP9, this feed forward pathway continues in an autoregulatory loop.⁴ Middle panel: in patients with a heterozygous mutation in BMPR2 leading to haploinsufficiency, cell surface BMPR-II is reduced and in its place, ActRII-A can form a complex with available ALK1 but this does not promote autoregulatory BMPR-II production in response to endogenous concentrations of BMP9, which remain unchanged. The reduced signalling through BMPR-II leads to reduced BMPR-II levels of the receptor at the cell surface. Right Panel: Administration of exogenous BMP9 to PAH patients with a heterozygous mutation in BMPR2, increases the circulating concentration of BMP9 which increases signalling via the Smad1/4 complex to induce BMPR-II protein expression. This shifts the equilibrium of the BMPR-II:ActR-IIA ratio in favour of BMPR-II associating with the available ALK1 and thus restores the autoregulatory production of BMPR-II in response to BMP9, thus restoring normal endothelial BMP9 signalling.