Together, these data demonstrate that EP300 directly activates NRP1 expression via H3K27 acetylation in PAECs and that NRP1, in turn, mediates VEGFR2-dependent signaling and mitochondrial gene expression, highlighting a novel epigenetic axis linking chromatin remodeling to endothelial dysfunction in PAH. The gene discussed is NRP1; the disease is pulmonary arterial hypertension.