Inhibition of BMPER Mitigates Pulmonary Hypertension by Modulating LRP1-YAP Interaction in Smooth Muscle Cells

BACKGROUND: BMPER (bone morphogenetic protein–binding endothelial regulator) is a secreted protein that is highly expressed in endothelial cells. It regulates the BMP (bone morphogenetic protein) pathway during vascular development and adulthood. Mutations in the BMP pathway are recognized as risk factors for pulmonary arterial hypertension group 1 pulmonary hypertension (PH). However, the roles of BMPER in pulmonary arterial hypertension remain unknown. METHODS: We assessed BMPER expression in Group 1 pulmonary arterial hypertension patient samples and examined its role in vascular remodeling using in vivo and in vitro approaches. RESULTS: BMPER level was elevated in pulmonary arterial hypertension lungs and significantly associated with pulmonary vascular resistance, but was not increased in patient plasma. Global and endothelial cell–specific depletion of BMPER in a mouse model of hypoxia-induced PH displayed attenuation in pulmonary artery smooth muscle cell proliferation, a hallmark of pulmonary vascular remodeling, and reduced right ventricular pressures. Conversely, adeno-associated virus–assisted BMPER overexpression targeted to the pulmonary endothelium led to the spontaneous development of PH. Mechanistically, BMPER promoted YAP (yes-associated protein 1) activation through the release of YAP sequestration by LRP1 (low-density lipoprotein receptor–related protein 1), a BMPER endocytic receptor, in the membrane of pulmonary artery smooth muscle cells. Moreover, the protective effect of BMPER depletion can be reversed by simultaneous depletion of LRP1 in mice with hypoxia-induced PH. CONCLUSIONS: Collectively, these results implicate secreted BMPER as a discrete regulator for pulmonary vascular remodeling and suggest its inhibition as a new potential therapeutic strategy against PH.