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Polymorphonuclear leukocytes (PMN) traverse an endothelial cell (EC) barrier by crawling between neighboring EC. Whether EC regulate the integrity of their intercellular adhesive and junctional contacts in response to chemotaxing PMN is unresolved. EC respond to the binding of soluble mediators such as histamine by increasing their cytosolic free calcium concentration (Ca++i) (Rotrosen, D., and J.I. Gallin. 1986. J. Cell Biol. 103:2379-2387) and undergoing shape changes (Majno, G., S. M. Shea, and M. Leventhal. 1969. J. Cell Biol. 42:617-672). Substances such as leukotriene C4 (LTC4) and thrombin, which increased the permeability of EC monolayers to ions, as measured by the electrical resistance of the monolayers, transiently increased EC Ca++i. To determine whether chemotaxing PMN cause similar changes in EC Ca++i, human umbilical vein endothelial cells (HUVEC) maintained as monolayers were loaded with fura-2. Ca++i was measured in single EC during PMN adhesion to and migration across these monolayers. PMN-EC adhesion and transendothelial PMN migration in response to formyl-methionyl-leucyl-phenylalanine (fMLP) as well as to interleukin 1 (IL-1) treated EC induced a transient increase in EC Ca++i which temporally corresponded with the time course of PMN-EC interactions. When EC Ca++i was clamped at resting levels with a cell permeant calcium buffer, PMN migration across EC monolayers and PMN induced changes in EC monolayer permeability were inhibited. However, clamping of EC Ca++i did not inhibit PMN-EC adhesion. These studies provide evidence that EC respond to stimulated PMN by increasing their Ca++i and that this increase in Ca++i causes an increase in EC monolayer permeability. Such Ca++i increases are required for PMN transit across an EC barrier. We suggest EC Ca++i regulates transendothelial migration of PMN by participating in a signal cascade which stimulates EC to open their intercellular junctions to allow transendothelial passage of leukocytes.
Huang et al. (Mon,) studied this question.