Loss of Caveolin‐1 Increases Macromolecule Transport Across Lymphatic Endothelium

Abstract

Transport of fluid and macromolecules from the interstitium into lymphatic vessels is necessary for maintaining tissue homeostasis. Lymphatic capillary structure suggests that passive, paracellular transport would be the predominate route of macromolecule entry into lymphatics. Active transcellular transport, however, was recently identified to be equally important to solute flux across lymphatic endothelium in vitro. To specifically test if loss of caveolar transport impacted lymphatic transport, lymphatic conductance and permeability were measured in mice with a global deletion of caveolin‐1 (“CavKO”), the scaffolding protein necessary for caveolae formation, and in mice with a lymphatic endothelial cell‐specific deletion of caveolin‐1 (Lyve1‐Cre x Cav1flox/flox; “LyCav”). In each mouse line, lymphatic capillary architecture was largely unchanged. Using a quantitative microlymphangiography model, lymphatic conductance (mm3 fluid uptake/mm3 tissue/time) was measured to be significantly higher in CavKO mice. Increased lymphatic conductance was also measured in CavKO mice following nitric oxide synthase inhibition and in LyCav mice with lymphatic‐specific loss of caveolae. The permeability to 70kDa dextran was significantly increased in monolayers of lymphatic endothelial cells isolated from CavKO mice. These findings confirm that macromolecule transport is increased with loss of caveolar trafficking. Interestingly, macromolecule transport within the lymphatic system, measured by transit rate of dextran to a sentinel lymph node, was significantly reduced in CavKO and LyCav mice and isolated vessel studies identified increased permeability of CavKO collecting lymphatic vessels resulting in macromolecule loss from the lumen. These studies identify lymphatic caveolar biology as a key regulator of active lymphatic transport functions.Support or Funding InformationThis research was supported by the Texas A&M University College of Medicine and Department of Medical Physiology.