Tissue homeostasis requires coordinated barrier function in blood and lymphatic vessels. Opening of junctions between endothelial cells (ECs) lining blood vessels leads to tissue fluid accumulation that is drained by lymphatic vessels. A pathological increase in blood vessel permeability or lack or malfunction of lymphatic vessels leads to edema and associated defects in macromolecule and immune cell clearance. Unbalanced barrier function between blood and lymphatic vessels contributes to neurodegeneration, chronic inflammation, and cardiovascular disease. In this proposal, we seek to gain mechanistic understanding into coordination of barrier function between blood and lymphatic vessels, how this process is altered in disease models and how it can be manipulated for therapeutic purposes. We will focus on two critical barriers with diametrically opposing functions, the blood-brain barrier (BBB) and the lymphatic capillary barrier (LCB). ECs of the BBB form very tight junctions that restrict paracellular access to the brain. In contrast, open junctions of the LCB ensure uptake of extravasated fluid, macromolecules and immune cells, as well as lipid in the gut. Using selective genetic manipulation in blood and lymphatic endothelium, respectively, of novel effectors of BBB and LCB junctions that we have identified, we will determine how function of the BBB and the LCB in adult homeostasis and in disease models is coordinated. Progress made during the initial grant period includes i) approaches to prevent neuroinflammation associated with BBB defects that develop in the face of a brain tumor, ii) identification of novel molecular approaches to manipulate the BBB, and iii) imaging of cranial lymphatic outflow in human patients using MRI. These pioneering studies promise to open up new opportunities for research and treatment of neurovascular and cardiovascular disease.
