A working hypothesis for the regulation of endothelial permeability, which was popular in the 1990s, states that signaling pathways that balance competing adhesive and contractile forces control the paracellular flux of macromol-ecules. Endothelial cell-cell and cell-matrix contacts tether endothelial cells to each other and to the extracellular matrix, respectively, and act against centripetal tension generated by actin-myosin motors. Thus, agents that enhance barrier function would do so by decreasing isometric tension; and the opposite would occur for barrier-decreasing agents. This hypothesis is supported by studies that have demonstrated that cAMP-enhancing agents increase barrier activity in association with decreases in myosin light-chain phosphorylation. The additional measurement of cellular isometric tension, however, provides a different conclusion in that cAMP-enhancing agents promote barrier function independently of cellular tension. In our hands, S1P and LPA increase endothelial barrier activity in association with increases in myosin light-chain phosphorylation and cellular isometric tension. S1P increases isometric cellar tension to a slightly lesser extent than can be induced by thrombin, which decreases endothelial barrier function. Thus, changes in cellular tension are not solely responsible for changes in barrier function as both S1P and cAMP increase barrier activity yet have opposite effects on myosin light-chain phosphorylation and cellular isometric tension.
cAMP-enhancing agents and S1P affect cellular targets that initiate cell spreading and alter the adherens junction proteins, cell-specific cadherins and catenins that mechanically hold cells together. An increase in intracellular cAMP causes the remodeling of actin filaments to the cell periphery and a concomitant loss of actin stress fibers. Spreading of adjacent cells resulting in closer apposition or overlap would increase the pathway for diffusive permeability. The simple act of cell spreading would counteract the cell retraction/contraction induced by barrier-loosening agents such as thrombin. S1P profoundly affects the actin cytoskeleton, inducing both stress fibers and an increase in peripheral actin within minutes. Whether this remodeling of actin influences cell spreading remains to be determined. Alternatively, changes in cortical actin may facilitate the stabilization of the adherens junction, and cAMP-enhancing agents and S1P may function by stabilizing junctions. An increase in intracellular cAMP has been shown to maintain within 10 minutes the transvascular flux of 3H inulin, transepithelial resistance, and the peripheral localization of E-cadherin and ZO-1 in the presence of low calcium in epithelial cells and to increase by 2 hours the peripheral localization of E-cadherin in brain microvascular endothelial cells. S1P has been shown to increase within 1 hour the localization of the adherens junction proteins, VE-cadherin and the catenins, a, b, and g, at the cell periphery and to increase the amount of VE-cadherin in the actin-associated cell fraction in human umbilical vein endothelial cells. These observations by Lee from the research laboratory of Hla  have led to the conclusion that S1P induces the formation of adherens junctions. Therefore, S1P and cAMP-enhancing agents may function to tighten the endothelial barrier at the level of the actin cytoskeleton and/or the adherens junction.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.