Exercise‐Induced Cardiac Lymphatic Remodeling Mitigates Inflammation in the Aging Heart
Kangsan Roh, Haobo Li, Rebecca Freeman, L. Zazzeron, Ahlim Lee, Charles Zhou, Siman Shen, Peng Xia, Justin Ralph Baldovino Guerra, Cedric Sheffield, Timothy P. Padera, Yirong Zhou, Sekeun Kim, Aaron D. Aguirre, Nicholas Houstis, Jason D. Roh, Fumito Ichinose, Rajeev Malhotra, Anthony Rosenzweig, James Rhee
Abstract
The lymphatic vasculature plays essential roles in fluid balance, immunity, and lipid transport. Chronic, low-grade inflammation in peripheral tissues develops when lymphatic structure or function is impaired, as observed during aging. While aging has been associated with a broad range of heart pathophysiology, its effect on cardiac lymphatic vasculature has not been characterized. Here, we analyzed cardiac lymphatics in aged 20-month-old mice versus young 2-month-old mice. Aged hearts showed reduced lymphatic vascular density, more dilated vessels, and increased inflammation and fibrosis in peri-lymphatic zones. As exercise has shown benefits in several different models of age-related heart disease, we further investigated the effects of aerobic training on cardiac lymphatics. Eight weeks of voluntary wheel running attenuated age-associated adverse remodeling of the cardiac lymphatics, including reversing their dilation, increasing lymph vessel density and branching, and reducing perilymphatic inflammation and fibrosis. Intravital lymphangiography demonstrated improved cardiac lymphatic flow after exercise training. Our findings illustrate that aging leads to cardiac lymphatic dysfunction, and that exercise can improve lymphatic health in aged animals.