Circular RNA profiling identifiescirc5078as aBMPR2-derived regulator of endothelial proliferation and stress responses

Germline loss-of-function BMPR2 mutations are the leading genetic cause of pulmonary arterial hypertension (PAH) and are strongly linked to aberrant endothelial proliferation and impaired translational stress responses. While these effects are generally attributed to a loss of the type-II bone morphogenetic protein receptor (BMPR-II), we used circular RNA profiling to identify circ5078 as a new functional RNA derived from exon 12 of the BMPR2 gene. circ5078 and linear BMPR2 mRNA exert opposing effects on endothelial proliferation and stress granule formation, driving impaired stress responses in PAH patient-derived endothelial cells that are deficient in linear BMPR2 transcripts, but not circ5078 . Rebalancing circular to linear transcript abundance by circ5078 depletion rescued stress granule formation in patient-derived endothelial cells, independent of BMPR-II protein levels. Polysome analysis demonstrated a reduction in free ribosomal subunits with the depletion of either linear or circular BMPR2 transcripts, and an accumulation of 80S monosomes exclusively with linear BMPR2 mRNA loss. These effects did not impact global protein synthesis or stress-induced eIF2α phosphorylation, but did alter the translational efficiency of multiple genes, including a group of nuclear encoded, mitochondrial ribosome proteins that were translationally enhanced with circ5078 silencing. Endothelial circ5078 depletion increased the efficiency of oxidative metabolism while reducing mitochondrial spare capacity, providing a potential link between mitochondrial function, proliferation and translational stress responses. Together, these findings reveal interdependent roles for linear and circular BMPR2 transcripts as functional contributors to the endothelial phenotype of PAH.