We applied CRISPRi to functionally validate candidate enhancers that we found are regulated by LSS, and are particularly relevant to pulmonary vascular homeostasis and PAH, i.e., BMPR2, SMAD5, and EDN1. We observed KLF4 binding at enhancers of other genes associated with PAH, such as ACVRL1, CAV1, ENG, SMAD9, and SOX17, but their expression levels did not significantly change under LSS. This evidence concerns the gene SMAD5 and pulmonary arterial hypertension.