KLF6 in Pulmonary Hypertension: The Dual Role of Friend and Foe

Background: Pulmonary arterial hypertension (PAH) is a severe lung condition with an unmet clinical need. Endothelial damage is followed by excessive repair and narrowing of lung arteries, but the mechanisms are unclear. Methods: We investigated the role of Kruppel-like transcription factor 6 (KLF6), known for its involvement in tissue injury response and cancer onset, in PAH through functional and expression analyses of human pulmonary artery endothelial cells (HPAECs) and PAH lung tissues. KLF6 activation patterns and transcriptional programs were compared with those regulated by KLF2 and KLF4, previously linked to PAH. Results: KLF6 expression increased due to hypoxic and inflammatory triggers in early rodent PAH. KLF6 overexpression improved endothelial survival and induced angiogenesis in cultured HPAECs and human pulmonary arterial explants. Transcriptomic analysis of KLF6-overexpressing HPAECs revealed its role in regulating endothelial homeostasis and expression of arterial identity genes, such as SOX17, ERG, BMPR2, KDR, TEK, ENG, ACVRL1 and CDH5. DisGeNET analysis showed a significant association of KLF6-regulated genes with PAH. Spatial transcriptomic analysis of PAH lung vascular tissues (n=6/group) revealed significant enrichment of KLF6-regulated genes in angiogenesis, cell motility, VEGFR signalling, and extracellular matrix organization. KLF6+ Erg+ vWF+ cells accumulated in vascular channels of remodelled PAH lungs and. KLF6 expression was elevated in PAH blood-derived endothelial progenitor cells (n=5) and pulmonary arterial cells in PAH associated with Alveolar Capillary Dysplasia. Conclusions: KLF6 uniquely orchestrates endothelial repair but its sustained activation promotes development of the apoptosis-resistant, angio-proliferative vascular phenotype in human PAH. Dysregulation of KLF6 signalling may have broader implications for pulmonary vascular disease.