Lymphatic Mechanoregulation in Development and Disease

Endothelial cells form the innermost layer of lymphatic and blood vessels and continuously interact with their luminal and tissue microenvironment. These interactions confer extracellular mechanical information, such as fluid shear stress, cellular stretch, and matrix stiffness, on the endothelium and are subsequently translated into intracellular biological responses. The impact of changes in fluid shear stress has been extensively studied in both lymphatic and blood endothelial cells. Recent studies suggest that the tissue microenvironment, which is established by the extracellular matrix, endothelial-associated mural cells, and the surrounding tissue, also fundamentally controls vascular development and disease.

In contrast to blood vessels, molecular mechanisms of lymphatic mechanoregulation via the tissue microenvironment are poorly understood. This review briefly compares what is known about the lymphatic and blood endothelial tissue microenvironment. We will further discuss how changes of the tissue microenvironment regulate lymphatic development and could contribute to dysregulation of lymphatic endothelial cells in disease. We aim to point out that a comprehensive analysis of tissue-regulated mechanisms could improve our understanding of lymphatic development and homeostasis and may eventually lead to the discovery of novel therapeutic approaches for lymphatic diseases associated with changes of the lymphatic-proximal microenvironment.