Lymphatic vessels maintain fluid homeostasis, transport dietary lipids and vitamins and contribute to immune surveillance by transporting soluble antigens and immune cells. Lymphatic vessels are also involved in many pathological conditions such as tumor metastasis and various inflammatory conditions. Dysfunction of lymphatic vessels leads to lymphedema, an accumulation of protein-rich fluid in interstitial space, resulting in swelling and fibrosis of the affected area. During the last decade signaling mechanisms involved in lymphatic vessel growth during development or tissue régénération have been a subject of intense research. Vascular Endothelial Growth Factor C (VEGFC) was identified as a key ligand that binds to lymphatic endothelial cell (LEC)-specific receptor tyrosine kinase, vascular endothelial growth factor receptor (VEGFR3), and induces LEC survival, prolifération and migration. In contrast, little is known about the pathways involved in lymphatic vessel maintenance and repair in adulthood. Adult lymphatic vasculature is considered to be essentially quiescent, with the exception of intestinal lymphatic capillaries.
Intriguingly, accumulating clinical reports link the use of rapamycin to the development of leg or arm lymphedema. Rapamycin, which is an inhibitor of mechanistic target of rapamycin (mTOR), is commonly used in kidney transplant patients to prevent graft rejection. Lymphedema was not observed in patients treated with other immunosuppressive regimens, such as calcineurin inhibitors. In this study, we have investigated the mechanisms in lymphatic vascular maintenance and repair. Our data show that main place for LEC renewal in mature adult vasculature is lymphatic collecting vessels and proliferating cells are mostly concentrated in valve région. Our work on mTOR demonstrates a new activation stimulus for mTOR signaling, which is flow shear stress. mTOR is found to be indispensable for LECs under shear stress and mTOR activity is required for protein synthesis and extracellular matrix (ECM) production, thus ensuring the integrity of LEC monolayer. This phenotype we have observed in LECs might explain the lymphedema observed in rapamycin treated transplant patients. Further studies will be performed to illuminate upstream and downstream molecular partners of mTOR signaling in lymphatics.