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

Tuder, Rubin M.; Gandjeva, Aneta; Williams, Sarah; Kumar, Sushil; Kheyfets, Vitaly O.; Hatton-Jones, Kyle Matthew; Starr, Jacqueline R.; Yun, Jeong; Hong, Jason; West, Nicholas P.; Stenmark, Kurt R.

doi:10.1164/rccm.202307-1310oc

Am J Respir Crit Care Med

2024

DOI: 10.1164/rccm.202307-1310oc

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

Rubin M. Tuder,

Aneta Gandjeva,

Sarah Williams

et al.

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Cited by 3 publications

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Classical dendritic cells contribute to hypoxia‐induced pulmonary hypertension

Mickael,

Sanders,

Lee

et al. 2024

The FASEB Journal

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Pulmonary hypertension (PH) is a chronic and progressive disease with significant morbidity and mortality. It is characterized by remodeled pulmonary vessels associated with perivascular and intravascular accumulation of inflammatory cells. Although there is compelling evidence that bone marrow‐derived cells, such as macrophages and T cells, cluster in the vicinity of pulmonary vascular lesions in humans and contribute to PH development in different animal models, the role of dendritic cells in PH is less clear. Dendritic cells' involvement in PH is likely since they are responsible for coordinating innate and adaptive immune responses. We hypothesized that dendritic cells drive hypoxic PH. We demonstrate that a classical dendritic cell (cDC) subset (cDC2) is increased and activated in wild‐type mouse lungs after hypoxia exposure. We observe significant protection after the depletion of cDCs in ZBTB46 DTR chimera mice before hypoxia exposure and after established hypoxic PH. In addition, we find that cDC depletion is associated with a reduced number of two macrophage subsets in the lung (FolR2+ MHCII+ CCR2+ and FolR2+ MHCII+ CCR2−). We found that depleting cDC2s, but not cDC1s, was protective against hypoxic PH. Finally, proof‐of‐concept studies in human lungs show increased perivascular cDC2s in patients with Idiopathic Pulmonary Arterial Hypertension (IPAH). Our data points to an essential role of cDCs, particularly cDC2s, in the pathophysiology of experimental PH.

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Classical dendritic cells contribute to hypoxia‐induced pulmonary hypertension

Mickael,

Sanders,

Lee

et al. 2024

The FASEB Journal

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Exploring the Molecular Signatures of Pulmonary Vascular Lesions

Oldham

2024

Am J Respir Crit Care Med

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Pathology and pathobiology of pulmonary hypertension: current insights and future directions

Guignabert,

Aman,

Bonnet

et al. 2024

Eur Respir J

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In recent years, major advances have been made in the understanding of the cellular and molecular mechanisms driving pulmonary vascular remodelling in various forms of pulmonary hypertension, including pulmonary arterial hypertension, pulmonary hypertension associated with left heart disease, pulmonary hypertension associated with chronic lung disease and hypoxia, and chronic thromboembolic pulmonary hypertension. However, the survival rates for these different forms of pulmonary hypertension remain unsatisfactory, underscoring the crucial need to more effectively translate innovative scientific knowledge into healthcare interventions. In these proceedings of the 7th World Symposium on Pulmonary Hypertension, we delve into recent developments in the field of pathology and pathophysiology, prioritising them while questioning their relevance to different subsets of pulmonary hypertension. In addition, we explore how the latest omics and other technological advances can help us better and more rapidly understand the myriad basic mechanisms contributing to the initiation and progression of pulmonary vascular remodelling. Finally, we discuss strategies aimed at improving patient care, optimising drug development, and providing essential support to advance research in this field.

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

Cited by 3 publications

References 55 publications

Classical dendritic cells contribute to hypoxia‐induced pulmonary hypertension

Classical dendritic cells contribute to hypoxia‐induced pulmonary hypertension

Exploring the Molecular Signatures of Pulmonary Vascular Lesions

Pathology and pathobiology of pulmonary hypertension: current insights and future directions

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