ROCK and cAMP promote lymphatic endothelial cell barrier integrity and modulate histamine and thrombin-induced barrier dysfunction

Jerome W Breslin
Lymphatic Research and Biology 2011, 9 (1): 3-11

BACKGROUND: There is recent evidence that inflammatory signals can modulate lymphatic vessel permeability, but current understanding of the mechanisms regulating lymphatic endothelial barrier function is limited. The objectives of this study were to 1) investigate whether inflammatory mediators that increase microvascular permeability also cause barrier dysfunction of lymphatic endothelial cell monolayers, and 2) determine the roles of signaling pathways that affect intercellular junctions and cell contraction in lymphatic endothelial barrier function.

METHODS AND RESULTS: Transendothelial electrical resistance (TER) of confluent adult human microlymphatic endothelial cells of dermal origin (HMLEC-d) served as an indicator of lymphatic endothelial barrier function. Human umbilical vein endothelial cells (HUVEC) were used to model blood-tissue barrier function. The inflammatory mediators histamine and thrombin each caused a decrease in TER of HMLEC-d and HUVEC monolayers, with notable differences between the two cell types. Treatment with 8-Br-cAMP enhanced HMLEC-d barrier function, which limited histamine and thrombin-induced decreases in TER. Blockade of myosin light chain kinase (MLCK) with ML-7 did not affect histamine or thrombin-induced decreases in TER. Treatment with the Rho kinase (ROCK) inhibitor Y-27632 caused a decrease in HMLEC-d barrier function.

CONCLUSIONS: These data show that inflammatory mediators can cause lymphatic endothelial barrier dysfunction, although the responses are not identical to those seen with blood endothelial cells. ROCK and cAMP both promote lymphatic endothelial barrier function, however ROCK appears to also serve as a mediator of histamine and thrombin-induced barrier dysfunction.

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