BMPR2 spruces up the endothelium in pulmonary hypertension

Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892,USA& Correspondence: jianhua.xiong@nih.gov (J. Xiong)Pulmonary hypertension (PH) is a potentially lethal disorderbecause of a dearth of effective therapeutic options(Schermuly et al., 2011; Mehari et al., 2014). Pulmonaryarterial hypertension (PAH) is a major type of PH that isdeﬁned by a mean pulmonary arterial pressure higher than25 mm Hg at rest or 30 mm Hg during exercise (Kovacset al., 2009). The majority of known genetic variationsassociated with PAH occur in bone morphogenetic proteinreceptor, type II (BMPR2), a type of transforming growthfactor (TGF)-β family of receptors. BMPR2 mutations areresponsible for the etiology of approximately 80% familialPAH and 30% idiopathic PAH (International P.P.H.C et al.,2000; Machado et al., 2006; Soubrier et al., 2013). Recenttranslational studies involving modulation of endothelialBMPR2 signaling have provided novel insights into treat-ment of PH, triggering a paradigm shift in our understandingof PH therapeutics (Fig. 1) (Long et al., 2015; Nickel et al.,2015; Prewitt et al., 2015).At the 5th World Symposium on PH held in 2013, anupdated clinical classiﬁcation of PH was agreed upon (Si-monneau et al., 2013). The current classiﬁcation categorizesPH into ﬁve groups sharing similar pathophysiologicalcharacteristics and treatment approaches: Group 1, PAH;Group 1′, pulmonary veno-occlusive disease and/or pul-monary capillary hemangiomatosis; Group 1′′, persistent PHof the newborn; Group 2, PH due to left heart disease; Group3, PH due to lung diseases and/or hypoxia; Group 4, chronicthromboembolic PH; Group 5, PH with unclear multifactorialmechanisms (Simonneau et al., 2013). Although PAH is arelatively rare disease, many genetic risk factors can sub-stantially enhance its incidence and prevalence with anincreased mortality (Peacock et al., 2007; Schermuly et al.,2011; Mehari et al., 2014). This is exempliﬁed by the iden-tiﬁcation of over 300 mutations of BMPR2, which account forapproximately 80% of patients with heritable PAH and 25%of patients with idiopathic PAH (Soubrier et al., 2013; Westet al., 2014).BMPR2 encodes a member of the TGF-β superfamily thatoperates in the TGF-β/bone morphogenetic protein (BMP)signal transduction pathways (International P.P.H.C et al.,2000; Soubrier et al., 2013). Intriguingly, pulmonary BMPR2expression is over expressed in vascular endothelium,implying that BMPRS plays a key role in endothelial dys-function underlying the development of PAH (Atkinson et al.,2002). As expected, heterozygous or homozygous BMPR2ablation in mouse pulmonary endothelium leads to PAH(Hong et al., 2008). BMPR2 haploinsufﬁciency is involved inthe pathobiology of PAH (Machado et al., 2001). Conditionalendothelial-speciﬁc expression of BMPR2 mutations in miceinduces a variety of PAH-related features including alteredpulmonary microvascular endothelial cell (EC) apoptosis,proliferation, inﬂammation and thrombosis (Majka et al.,2011). Therefore, it is rational to consider activating and/orrestoring a physiological balance of BMPR2 signaling foroptimal treatment of PAH.To assess the efﬁcacy of BMP ligands in selectively tar-geting endothelial BMPR2 signaling, Long and colleaguesgenerated a BMPR2-deﬁcient mouse PAH model andexamined two rat PAH models in response to eithermonocrotaline or vascular endothelial growth factor receptorblockade and hypoxia (Sugen-hypoxia) (Long et al., 2015).Initial results demonstrated that administration of BMP9 iscapable of reversing PAH in these rodents. Consistent withthis, enhancement of endothelial BMPR2 signaling by BMP9is highly effective in preventing apoptosis and maintainingbarrier integrity of pulmonary arterial endothelial cells(PAECs) from PAH patients bearing BMPR2 mutations. Thislends further support to the idea that manipulation of BMPR2signaling is a promising clinical strategy for the treatment ofPAH (Long et al., 2015). Another BMP ligand, BMP2 has a