Digital Spatial Profiling Identifies Distinct Molecular Signatures of Vascular Lesions in Pulmonary Arterial Hypertension

• DOI: 10.1164/rccm.202307-1310oc
• Publication Date: 2024-04-03T15:16:43Z
• Authors: Rubin M. Tuder; Aneta Gandjeva; Sarah Williams; Sushil Kumar; Vitaly O. Kheyfets; Kyle Matthew Hatt...; Jacqueline R. Starr; Jeong Yun; Jason Hong; Nicholas P. West; Kurt R. Stenmark
• Keywords: Adventitia

Rationale: Idiopathic Pulmonary Arterial Hypertension (IPAH) is characterized by extensive pulmonary vascular remodeling due to plexiform and obliterative lesions, media hypertrophy, inflammatory cell infiltration, alterations of the adventitia. Objective: Test hypothesis that microscopic IPAH lesions express unique molecular profiles, which collectively are different from control arteries. Methods: We used digital spatial transcriptomics profile genome-wide differential transcriptomic signature key pathological (plexiform, obliterative, intima+media adventitia) in lungs (n= 11) compared these data adventitia artery (n=5). Results: detected 8273 transcripts lung Plexiform exhibited greatest number differentially expressed genes when with intima-media hypertrophy lesions. showed enrichment for (i) associated TGFβ-signaling (ii) mutated affecting extracellular matrix endothelial-mesenchymal transformation. upregulation involved immune interferon signaling, coagulation, complement pathways. Cellular deconvolution indicated variability cells between underlies transcript profiling. Conclusions: profiles enriched pathways involving pathogenetic pathways, including genetic disease drivers, innate acquired immunity, hypoxia sensing, angiogenesis signaling. These provide a rich molecular-structural framework inform novel biomarkers therapeutic targets this highly morbid disease.