Arterial lymphatics in atherosclerosis: Old questions, new insights, and remaining challenges

The lymphatic network is well known for its role in the maintenance of tissue fluid homeostasis, absorption of dietary lipids, trafficking of immune cells, and adaptive immunity. Aberrant lymphatic function has been linked to lymphedema and immune disorders for a long time. Discovery of lymphatic cell markers, novel insights into developmental and postnatal lymphangiogenesis, development of genetic mouse models, and the introduction of new imaging techniques have improved our understanding of lymphatic function in both health and disease, especially in the last decade. Previous studies linked the lymphatic vasculature to atherosclerosis through regulation of immune responses, reverse cholesterol transport, and inflammation. Despite extensive research, many aspects of the lymphatic circulation in atherosclerosis are still unknown and future studies are required to confirm that arterial lymphangiogenesis truly represents a therapeutic target in patients with cardiovascular disease. In this review article, we provide an overview of factors and mechanisms that regulate lymphangiogenesis, summarize recent findings on the role of lymphatics in macrophage reverse cholesterol transport, immune cell trafficking and pathogenesis of atherosclerosis, and present an overview of pharmacological and genetic strategies to modulate lymphatic vessel density in cardiovascular tissue.