Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension

Abstract

Since its association with familial pulmonary arterial hypertension (PAH) in 2000, Bone Morphogenetic Protein Receptor II (BMPR2) and its related signaling pathway have become recognized as a key regulator of pulmonary vascular homeostasis. Herein, we define BMPR2 deficiency as either an inactivation of the receptor, decreased receptor expression, or an impairment of the receptor’s downstream signaling pathway. Although traditionally the phenotypic consequences of BMPR2 deficiency in PAH have been thought to be limited to the pulmonary vasculature, there is evidence that abnormalities in BMPR2 signaling may have consequences in many other organ systems and cellular compartments. Revisiting how BMPR2 functions throughout health and disease in cells and organs beyond the lung vasculature may provide insight into the contribution of these organ systems to PAH pathogenesis as well as the potential systemic manifestation of PAH. Here we review our knowledge of the consequences of BMPR2 deficiency across multiple organ systems.

Plasma metabolomics exhibit response to therapy in chronic thromboembolic pulmonary hypertension

“…While well established in heart failure [39] there is also a growing body of evidence that perturbations in systemic metabolism are involved in the pathogenesis of PAH and CTEPH [40].…”

MnTBAP Reverses Pulmonary Vascular Remodeling and Improves Cardiac Function in Experimentally Induced Pulmonary Arterial Hypertension

“…Heterozygous germ-line mutations in BMPR2, a gene encoding the bone morphogenetic protein (BMP) type 2 receptor, are the most common causal factors in hPAH [9]. Interestingly, in both hPAH and iPAH, a reduction in BMPR2 expression in ECs has been reported [10][11][12]. Besides, since not all individuals carrying mutations in BMPR2 will develop PAH, environmental factors including hypoxia and inflammation may provide local triggers for the disease [13][14][15][16][17].…”

Targeting BMPR2 Trafficking with Chaperones: An Important Step toward Precision Medicine in Pulmonary Arterial Hypertension

“…BMPR2 (Bone Morphogenetic Protein Receptor 2) is recognized as a key signaling pathway receptor and potential master switch in PAH. Reduced BMPR2 expression and dysfunctional signaling recapitulate, in vitro , many of the above cellular derangements attributed to PAH pathogenesis ( 2 ). The BMPR2 pathway became the focus of the PAH research community 20 years ago when two independent groups described BMPR2 loss-of-function mutations as the disease-causing mutations in hereditary PAH ( 3 , 4 ).…”

“…Criticism regarding targeting BMPR2 in PAH stems from the fact that only ∼20% of patients with PAH harbor a BMPR2 mutation and that BMPR2 mutations show an incomplete penetrance (20–30%), implying that other genetic and environmental factors might equally contribute to the disease pathogenesis. However, it is apparent that patients with idiopathic or associated PAH without a BMPR2 mutation have reduced BMPR2 expression in the lung and blood cells, again stimulating a concerted effort to augment or rescue the BMPR2 pathway for therapy ( 2 , 9 ). Although gene therapy was successful in animal models of PH, these approaches still face obstacles before they can be used in patients with PAH ( 10 ).…”