Abstract
Lymphatic vascular permeability prevents lymph leakage that is associated with lymphedema, lymphatic malformations, obesity, and inflammation. However, the molecular control of lymphatic permeability remains poorly understood. Recent studies have suggested that adherens junctions and vesicle transport may be involved in regulating lymphatic vessel permeability. To determine the contribution of each transport pathway, we utilized an ex vivo permeability assay to directly measure the solute flux of various molecular weight solutes across a range of pressures in intact murine collecting lymphatic vessels. Pharmacological and biological tools were used to probe the relative contributions of vesicles and junction proteins in the lymphatic vasculature. We show that the permeability of collecting lymphatic vessels is inversely related to the solute molecular weight. Further, our data reveal that vesicles selectively transport BSA, as an inhibitor of vesicle formation significantly decreased the permeability to BSA (∼60% decrease, n = 8, P = 0.02), but not to 3 kDa dextran (n = 7, P = 0.41), α-lactalbumin (n = 5, P = 0.26) or 70 kDa dextran (n = 8, P = 0.13). In contrast, disruption of VE-cadherin binding with a function blocking antibody significantly increased lymphatic vessel permeability to both 3 kDa dextran (5.7-fold increase, n = 5, P < 0.0001) and BSA (5.8-fold increase, n = 5, P < 0.0001). Thus, in the lymphatic vasculature, adherens junctions did not exhibit selectivity for any of the solutes tested here, whereas vesicles specifically transport BSA. Overall, the findings suggest that disease states that disrupt VE-cadherin localization or expression will cause significant leakage of solutes and fluid from the lymphatic vasculature.
Highlights
The lymphatic vasculature constantly removes the capillary filtrate from the tissues and returns this protein-rich fluid to the blood circulation, thereby preventing fluid accumulation in the form of edema
For imaging VE-cadherin, vessels were treated with either vehicle (DMSO) or dynasore (100 μM) for 30 min, or with IgG isotype control or BV13 (100 μg) for 4 h and Lymphatic Vessel Permeability Is Dependent on Solute Size and Pressure
Over the past decade, our studies have demonstrated that collecting lymphatic vessels in vivo and ex vivo are permeable, with a permeability to albumin similar to that of post-capillary venules ∼3 × 10−7 cm s−1, and leak solute from the lumen into the surrounding tissue due to their high hydrostatic pressure (Scallan and Huxley, 2010; Scallan et al, 2015)
Summary
The lymphatic vasculature constantly removes the capillary filtrate from the tissues and returns this protein-rich fluid to the blood circulation, thereby preventing fluid accumulation in the form of edema. The permeability of the lymphatic vasculature must be tightly regulated. Recent studies have demonstrated that the permeability of the lymphatic vasculature extends beyond mere fluid balance, with major roles in several vascular diseases. Dysregulated lymphatic vascular permeability is most observed as lymph leakage. Lymphatic vessel leakage is a hallmark of lymphatic malformations, which are aberrant growths of the lymphatic vasculature caused by somatic or congenital gene mutations (Brouillard et al, 2014; Ozeki and Fukao, 2019). Gene mutations that disrupt lymphatic vascular permeability cause congenital lymphedema (Lapinski et al, 2012; Sabine et al, 2015), a disease characterized by incurable tissue swelling. Dysregulated lymphatic vascular permeability has been associated with impaired immune responses as a consequence of prior infection (Fonseca et al, 2015)
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