Proximal Pulmonary Artery Stiffening as a Biomarker of Cardiopulmonary Aging

The geroscience hypothesis suggests that understanding mechanisms underlying aging will enable us to delay and lessen age-related disability and diseases. The role of mechanical factors has been increasingly appreciated in many aspects of the aging process. Here, we use mouse models to investigate changes in the biomechanics of the proximal pulmonary artery, lung function, and right ventricle function in aging. We found an age-related decreased capacity to store energy and increased circumferential stiffness of the proximal pulmonary artery with age that is associated with a reorientation of collagen toward the circumferential direction, decreased exercise ability, and decreased function of the lung and right ventricle. The observed compromised mechanics in the proximal pulmonary artery are consistent across multiple mouse models of accelerated aging. Furthermore, transcriptional changes in the 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 TGFβ pathway) and increased intercellular signaling amongst perivascular macrophages, fibroblasts, and smooth muscle cells. Our results provide promising biomarkers of aging for diagnosis and potential pathways and molecular targets for antiaging therapies.