Proximal Pulmonary Artery Stiffening as a Biomarker of Cardiopulmonary Aging

De Man, R.; Cai, Z.; Doddaballapur, P.; Guerrera, N.; Lin, L.; Justet, A.; Abu Hussein, N. S.; Cavinato, C.; Raredon, M. S. B.; Heerdt, P.; Singh, I.; Yan, X.; Kang, M.-J.; Bruns, D. R.; Lee, P. J.; Tellides, G.; Humphrey, J.; Kaminski, N.; Ramachandra, A. B.; Manning, E. P.

doi:10.1101/2025.06.10.658632

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bioRxiv · 10.1101/2025.06.10.658632

Proximal Pulmonary Artery Stiffening as a Biomarker of Cardiopulmonary Aging

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Abstract

The geroscience hypothesis suggests that understanding underlying ageing mechanisms will enable us to delay aging and lessen age-related disability and diseases. While hallmarks of ageing list multiple contributing factors, role of mechanics has only been recently recognized and increasingly appreciated. Here, we use mouse models of ageing to investigate changes in mechanics of the proximal pulmonary artery, lung and right ventricle function in ageing. We found an age-related decline in the capacity to store energy and increased circumferential stiffness of the proximal pulmonary artery with age that associated with a reorientation of collagen towards the circumferential direction, decreased exercise ability, and decreased function of the lung and right ventricle. The observed compromised mechanics in proximal pulmonary artery is consistent across multiple mouse models of accelerated ageing. Further, transcriptional changes in proximal pulmonary artery indicate that aging is associated with senescence of perivascular macrophages, adventitial fibroblasts, and medial smooth muscle cells. Older pulmonary arteries increase expression of genes associated with ECM turnover (including genes in the TGF{beta} pathway) and increased intercellular signaling amongst perivascular macrophages, fibroblasts and smooth muscle cells. Our results provide promising biomarkers of ageing for diagnosis and potential pathways and molecular targets for targeting anti-ageing therapies.

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De Man, R., Cai, Z., Doddaballapur, P., Guerrera, N., Lin, L., Justet, A., Abu Hussein, N. S., Cavinato, C., Raredon, M. S. B., Heerdt, P., Singh, I., Yan, X., Kang, M.-J., Bruns, D. R., Lee, P. J., Tellides, G., Humphrey, J., Kaminski, N., Ramachandra, A. B., Manning, E. P.. 2025-06-15. Proximal Pulmonary Artery Stiffening as a Biomarker of Cardiopulmonary Aging. https://doi.org/10.1101/2025.06.10.658632

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