BMPR2 mutations and endothelial dysfunction inpulmonary arterial hypertension (2017 Grover Conference Series)

摘要

Despite the discovery more than 15 years ago that patients with hereditary pulmonary arterial hypertension (HPAH) inherit BMP type 2 receptor (BMPR2) mutations, it is still unclear how these mutations cause disease. In part, this is attributable to the rarity of HPAH and difficulty obtaining tissue samples from patients with early disease. However, in addition, limitations to the approaches used to study the effects of BMPR2 mutations on the pulmonary vasculature have restricted our ability to determine how individual mutations give rise to progressive pulmonary vascular pathology in HPAH. The importance of understanding the mechanisms by which BMPR2 mutations cause disease in patients with HPAH is underscored by evidence that there is reduced BMPR2 expression in patients with other, more common, non-hereditary form of PAH, and that restoration of BMPR2 expression reverses established disease in experimental models of pulmonary hypertension. In this paper, we focus on the effects on endothelial function. We discuss some of the controversies and challenges that have faced investigators exploring the role of BMPR2 mutations in HPAH, focusing specifically on theeffects different BMPR2 mutation have on endothelial function,and whether there are qualitative differences between differentBMPR2 mutations. We discuss evidence that BMPR2 signalingregulates a number of responses that may account for endothelial abnormalitiesin HPAH and summarize limitations of the models that are used to study theseeffects. Finally, we discuss evidence that BMPR2-dependenteffects on endothelial metabolism provides a unifying explanation for the manyof the BMPR2 mutation-dependent effects that have beendescribed in patients with HPAH.