Transcription factor SOX17 plays a key role in vascular development and is a crucial genetic risk factor of the incurable disease pulmonary arterial hypertension (PAH), with both rare and common genetic risk variants. The disease is caused by obstructive vascular remodelling initiated by the dysfunction of pulmonary artery endothelial cells (PAEC).

We hypothesize that SOX17 dysregulation leads to PAEC dysfunction, which can be rescued by restoring SOX17 or downstream targets. To achieve this, we performed multi-omic analyses to identify novel targets of SOX17. Our results were passed into the LINCS drug:gene expression database to predict therapeutic compounds.

We have demonstrated that SOX17 loss alters PAEC proliferation, apoptosis and permeability (Walters R, et al. 2023, Circulation). Our PAEC-SOX17 ChIP-seq identified 4605 genes with SOX17 binding at regulatory elements. Expression of 262/4605 genes was also affected by SOX17 manipulation by overexpression/siRNA and 9/262 genes encode proteins whose levels were associated with the SOX17 common disease risk variants in PAH patients? plasma. LINCS predicted 7 therapeutic compounds and qPCR analysis of PAEC indicated compounds reinstated gene expression. Increased PAEC proliferation due to SOX17 loss was rescued by two compounds.

SOX17 dysregulation drives PAEC dysfunction, a key feature of PAH, and compounds that reinstate SOX17 target genes may be able to restore physiologic PAEC function.