Longitudinal spatial transcriptomics reveals the molecular dynamics of pulmonary artery remodeling in pulmonary arterial hypertension

The pathophysiology of pulmonary artery (PA) remodeling in pulmonary arterial hypertension (PAH) remains poorly understood. We performed the first longitudinal spatial transcriptomics analysis in a PAH patient who underwent sequential lung transplantations 13 years apart to uncover the temporal dynamics of the vascular lesions in PAH. We profiled the whole transcriptome in precisely defined regions, including small (20-500 µm) and large (>500 µm) PAs, at 2 time points representing severe and moderate remodeling. Spatial analysis revealed profound transcriptomic differences between small and large PAs in the severely remodeled lesions. Longitudinal comparison identified a 115-gene remodeling signature unique to severely affected small PAs, which was also enriched in independent PAH cohorts. A refined 25-gene core signature functionally linked to cell development pathways exhibited an even stronger association with PAH. This spatio-temporal analysis provides molecular insight into PA remodeling dynamics and identifies gene signatures that may guide development of targeted therapies.