GSE192649
E2F1 mediates SOX17 Deficiency-Induced Pulmonary Hypertension
SRY-Box Transcription Factor 17 (SOX17) enhancers variants and mutations are found in patients with pulmonary arterial hypertension (PAH). In human PAH pulmonary microvascular endothelial cells (HPMVEC), there is a significant downregulation of SOX17 expression. We hypothesized that SOX17 deficiency contributes to the pathogenesis of PAH and found that mice with endothelial specific disruption (ecKO Sox17) developed spontaneous pulmonary hypertension (PH) and exacerbated hypoxia-induced PH. Loss of SOX17 in lung ECs induces cell cycle programming, proliferative and anti-apoptotic phenotypes, a process mediated by the activation of E2F Transcription Factor 1 (E2F1) signaling. Pharmacological inhibition of E2F1 in ecKO Sox17 mice attenuated PH and cell cycle programming. Our study demonstrated that endothelial SOX17 deficiency induces PH and targeting E2F1 signaling represents a promising approach in PAH patients. Overall design: Human lung microvascular endothelial cells were knocked down with siRNA against SOX17 or control for 48 hours. Equal amount of RNA from three replicates per condition was pooled together for RNA sequencing analysis.