KLF6 activation marks an angiogenic and apoptosis resistant endothelial phenotype in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a severe, currently incurable lung disease characterized by endothelial injury and excessive repair, leading to arterial narrowing. However, the contributory mechanisms remain poorly understood. Here we show that Krüppel-like factor 6 (KLF6) is a feature of vascular pathology in PAH. KLF6 expression is elevated in human PAH and preclinical models of PAH and promotes endothelial repair and angiogenesis through transcriptomic remodelling, with effects distinct from those of KLF2 and KLF4. Endothelial KLF6 also stimulates vascular smooth muscle cell proliferation, which is attenuated by bosentan and imatinib. DisGeNET and spatial transcriptomic analyses of control and PAH lungs reveal elevated KLF6 in PAH endothelium, endothelial progenitor cells, and PAH with alveolar capillary dysplasia. In summary, KLF6 activation uniquely orchestrates endothelial repair and is a feature of the angio-proliferative vascular phenotype in PAH.