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

Science and Research

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). Idiopathic pulmonary hypertension (IPAH for short) is a chronic disease that can lead to severe breathing difficulties and a higher risk of heart damage or other life-threatening complications. While drugs exist to help manage symptoms, none are currently curative. IPAH mainly affects the pulmonary arteries, which are tasked with carrying the blood from the heart to the lungs to collect oxygen. The disease causes the walls of these vessels to thicken abnormally, obstructing blood flow and requiring the heart to work harder. The outer layers of pulmonary arteries are formed of both fibroblast and smooth muscle cells: the fibroblasts produce proteins that support the structure of the vessel, while the smooth muscle helps control blood flow by contracting and relaxing. Both types of cells are involved in vessel wall thickening in IPAH, but what causes them to switch from a healthy to a diseased state remains unclear. To examine this question, Crnkovic et al. compared the gene activity, protein production and behaviour of smooth muscle cells and fibroblasts obtained from the pulmonary arteries of healthy donors and IPAH patients. The experiments revealed that both types of cells showed similar impairments to their mitochondria, the cellular structures that help provide energy. However, differences also emerged. Diseased smooth muscle tissue produced the proteins that these cells use to contract and relax, ultimately impairing their ability to regulate blood flow to the lungs. Meanwhile, IPAH fibroblasts multiplied abnormally fast, potentially contributing to vessel thickening. Growing smooth muscle and fibroblast cells together in the laboratory allowed Crnkovic et al. to examine how interactions between these cells could help drive the disease. This showed that the fibroblasts released signals which triggered IPAH-characteristic changes in normally healthy smooth muscle cells. As such, the ability of fibroblasts to ‘talk’ to smooth muscle cells could be important in the progression of the condition. Crnkovic et al. hope that these findings will help develop better treatments to stop or reverse the progression of IPAH. However, further research is needed to confirm which biological processes should be targeted, and to ensure that reversing the abnormal changes in lung blood vessels is both safe and effective. eng