Adventitial fibroblasts direct smooth muscle cell-state transition in pulmonary vascular disease

Adventitial fibroblasts direct smooth muscle cell-state transition in pulmonary vascular disease

Background: Pulmonary vascular remodeling is a progressive pathological process characterized by functional alterations within pulmonary artery smooth muscle cells (PASMCs) and adventitial fibroblasts (PAAFs). Mechanisms driving the transition to a diseased phenotype remain elusive. Methods: We comb...

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Main Authors: Slaven Crnkovic, Helene Thekkekara Puthenparampil, Shirin Mulch, Valentina Biasin, Nemanja Radic, Jochen Wilhelm, Marek Bartkuhn, Ehsan Bonyadi Rad, Alicja Wawrzen, Ingrid Matzer, Ankita Mitra, Ryan D Leib, Bence Miklos Nagy, Anita Sahu-Osen, Francesco Valzano, Natalie Bordag, Matthias Evermann, Konrad Hoetzenecker, Andrea Olschewski, Senka Ljubojevic-Holzer, Malgorzata Wygrecka, Kurt Stenmark, Leigh M Marsh, Vinicio de Jesus Perez, Grazyna Kwapiszewska
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2025-04-01
Series:eLife
Subjects:
pulmonary artery
adventitial fibroblasts
vascular smooth muscle cells
Online Access:https://elifesciences.org/articles/98558
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Summary:Background: Pulmonary vascular remodeling is a progressive pathological process characterized by functional alterations within pulmonary artery smooth muscle cells (PASMCs) and adventitial fibroblasts (PAAFs). Mechanisms driving the transition to a diseased phenotype remain elusive. Methods: We combined transcriptomic and proteomic profiling with phenotypic characterization of source-matched cells from healthy controls and individuals with idiopathic pulmonary arterial hypertension (IPAH). Bidirectional cellular crosstalk was examined using direct and indirect co-culture models, and phenotypic responses were assessed via transcriptome analysis. Results: PASMC and PAAF undergo distinct phenotypic shifts during pulmonary vascular remodeling, with limited shared features, such as reduced mitochondrial content and hyperpolarization. IPAH-PASMC exhibit increased glycosaminoglycan production and downregulation of contractile machinery, while IPAH-PAAF display a hyperproliferative phenotype. We identified alterations in extracellular matrix components, including laminin and collagen, alongside pentraxin-3 and hepatocyte growth factor, as potential regulators of PASMC phenotypic transitions mediated by PAAF. Conclusions: While PASMCs and PAAFs retain their core cellular identities, they acquire distinct disease-associated states. These findings provide new insights into the dynamic interplay of pulmonary vascular mesenchymal cells in disease pathogenesis. Funding: This work was supported by Cardio-Pulmonary Institute EXC 2026 390649896 (GK) and Austrian Science Fund (FWF) grant I 4651-B (SC).
ISSN:2050-084X

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