ILLUMINATING MOLECULAR REGULATORS OF LYMPHATIC ENDOTHELIAL CELL SIGNALING AND IDENTITY

The lymphatic vasculature is unidirectional conduit that transports lymph throughout the body, participates in immune surveillance, lipid absorption and fluid homeostasis. Cardiac lymphatics are uniquely adapted to the microenvironment of the heart to maintain tightly regulated fluid homeostasis. These vessels are highly sensitive to disturbances caused by cardiovascular disease and can contribute to the development of myocardial edema. Thus, a complex interplay between lymphatics, myocardial edema, and cardiovascular disease has garnered a tidal wave of new discoveries and promises for therapeutic advances, discussed in Chapter 1. Lymphatic vessels are highly dynamic and have been found to have a diverse range of organ specific functions conferred to them by the recruitment of specific protein interaction networks to affect a range of signaling pathways. The adherens junction protein vascular endothelial cadherin (VE-cadherin), which controls inter-endothelial permeability and vascular integrity has recently been shown to have differential requirements across lymphatic beds. In Chapter 2, VE-cadherin is shown to be essential for cardiac lymphatic maintenance through the formation of a stable lymphatic signaling node. Chapter 3 explores the unique network of VE-cadherin interacting proteins and how this network changes during adherens junction rearrangement and influences a range of predicted and unpredicted molecular pathways. Chapter 4 explores the therapeutic potential of lymphatics in disease and how strategies of activating or inhibiting the growth of new lymphatic vessels have had both successes and failures. Further, this chapter explores the molecular characteristics of the lymphatic system which makes it an ideal conduit for drug delivery and highlights potential modulatory targets. Chapter 5 offers concluding remarks on the state and future of lymphatic research and medicine.