Rescuing the BMPR2 signaling axis in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a lethal disorder characterized by pulmonary arterial remodeling, increased right ventricular systolic pressure (RVSP), vasoconstriction and inflammation. The heritable form of PAH (HPAH) is usually (>80%) caused by mutations in the bone morphogenic protein receptor 2 (BMPR2) gene. Existing treatments for PAH typically focus on the end-stage sequelae of the disease, but do not address underlying mechanisms of vascular obstruction and blood flow and thus, in the long run, have limited effect because they treat the symptoms rather than the cause. Over the past decade, improved understanding of the molecular mechanisms behind the disease has enabled us to consider several novel therapeutic pathways. These include approaches directed toward BMPR2 gene expression, alternative splicing, downstream BMP signaling, metabolic pathways and the role of estrogens and estrogenic compounds in BMP signaling. It is likely that, ultimately, only one or two of these pathways will generate meaningful treatment options, however the potential benefits to PAH patients are still likely to be significant.