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.
Highlights
20 years ago, genetic linkage studies connected Bone Morphogenetic Protein Receptor II (BMPR2) to the development of familial pulmonary arterial hypertension (PAH) [1,2]
Given the relationship between non-Bone Morphogenetic Proteins (BMPs) transforming growth factor (TGF)-β signaling and cardiac interstitial fibrosis in the left ventricle, it is compelling to ask if BMPR2 deficiency imparts a further maladaptive response in the hypertensive Right ventricular (RV), which is the topic of active investigations
After the discovery that loss of BMPR1A leads to the development of Juvenile Polyposis [137], it was suggested that BMP signaling is tumor suppressive while classic TGF-β signaling is implicated in cancer pathogenesis
Summary
20 years ago, genetic linkage studies connected Bone Morphogenetic Protein Receptor II (BMPR2) to the development of familial pulmonary arterial hypertension (PAH) [1,2]. The pathway is complexly regulated at multiple levels by auxiliary co-receptors (Endoglin), pseudoreceptors (BMP and Activin Membrane-Bound Inhibitor, BAMBI), BMP antagonists (Noggin, Gremlin-1, Chordin), and inhibitory SMAD proteins (SMAD6, 7), reviewed in [5]. Beyond heterozygous BMPR2 germ line mutations in familial PAH, both idiopathic PAH and associated PAH (APAH) due to interstitial lung disease, connective tissue disease, or congenital heart disease are associated with lower levels of BMPR2 expression and signaling [20,21]. In PAH, a disease with multiple cell types involved, signaling pathways implicated, and temporal dynamics at play, the strong genetic association with BMPR2 creates a key opportunity for developing and testing therapeutic interventions. The pathway is complexly regulated at multiple levels by auxiliary co-receptors (Endoglin), pseudoreceptors (BMP and Activin Membrane-Bound Inhibitor, BAMBI), BMP antagonists (Noggin, Gremlin-1, Chordin), and inhibitory SMAD proteins
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