Reactive Oxygen Species in Regulating Lymphangiogenesis and Lymphatic Function

Abstract

The lymphatic system is pivotal for immunosurveillance and the maintenance of tissue homeostasis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vessels, has both physiological and pathological roles. Recent advances in the molecular mechanisms regulating lymphangiogenesis have opened a new area of research on reparative lymphangiogenesis for the treatment of various pathological disorders comprising neurological disorders, cardiac repair, autoimmune disease, obesity, atherosclerosis, etc. Reactive oxygen species (ROS) produced by the various cell types serve as signaling molecules in several cellular mechanisms and regulate various aspects of growth-factor-mediated responses, including lymphangiogenesis. The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. Low ROS levels are essential for lymphangiogenesis. On the contrary, oxidative stress due to enhanced ROS generation and/or reduced levels of antioxidants suppresses lymphangiogenesis via promoting lymphatic endothelial cell apoptosis and death. In this review article, we provide an overview of types and sources of ROS, discuss the role of ROS in governing lymphangiogenesis and lymphatic function, and summarize the role of lymphatics in various diseases.

Keywords: hydrogen peroxide; lymphangiogenesis; lymphatic vessels; nitric oxide; reactive oxygen species; superoxide anion.

Figure 1

Role of ROS in regulating lymphangiogenesis and lymphatic function. Activation of VEGFR3 present in LECs by its ligand VEGF-C induces optimal Nox4-derived H₂O₂ production, which in turn enhances VEGFR3 autophosphorylation and stimulates downstream pro-lymphangiogenic signaling (upper panel). Oxidized LDL and RSPO2 inhibit lymphangiogenesis via suppression of Akt/eNOS pathway. Under diabetic condition, excessive H₂O₂ generation elevates epsin expression and promotes VEGFR3 degradation, leading to attenuated lymphangiogenesis and reduced lymphatic transport. In inflammatory condition, supra-physiological NO production by CD11b⁺ myeloid immune cells surrounding LVs contributes to nitrosative stress leading to the suppression of lymphatic contractions and inducing LV leakiness (lower panel).

Figure 2

Role of the lymphatic system in health and disease.