Endothelial barrier integrity is maintained by adhesive interactions occurring at the cell-cell and cell-matrix contacts via junctional proteins and focal adhesion complexes that are anchored to the cytoskeleton. Under physiological conditions, cyclic AMP and PKA counteract with the NO-PKG pathway to protect the basal barrier function. Upon stimulation by physical stress, growth factors, or inflammatory agents, endothelial cells undergo a series of intracellu-lar signaling reactions involving activation of PKC, PKG, MAPKs, and PTKs. These protein kinases further trigger biochemical and conformational changes in the barrier structure and ultimately lead to an opening of the paracellu-lar pathway. In particular, MLCK activation and subsequent MLC phosphorylation in endothelial cells directly result in cell contraction and shape changes. The PTK-mediated phosphorylation of junctional proteins causes disorganization of adherens junctions or dissociation of VE-cadherin-catenin complex from its cytoskeletal anchor, leading to loose or opened intercellular junctions. Additionally, FAK phosphorylation-coupled focal adhesion assembly and redistribution provide an anchorage support for the con-formational changes occurring in the cells and at the cell junctions. The Src-family tyrosine kinases may serve as a common signal that coordinates these molecular events to facilitate the paracellular transport of macromolecules. The critical roles of protein kinases in the endothelial hyperper-meability response implicate the therapeutic significance of protein kinase inhibitors in the prevention and treatment of diseases and injuries that are associated with microvascular barrier dysfunction.

Further Readings

Baldwin, A. L., and Thurston, G. (2001). Mechanics of endothelial cell architecture and vascular permeability. Crit. Rev. Biomed. Eng. 29, 247-278.

Dudek, S. M., and Garcia, J. G. (2001). Cytoskeletal regulation of pulmonary vascular permeability. J. Appl. Physiol. 91, 1487-1500. Dr. Joe

Garcia and his colleagues are leading investigators in the molecular control of pulmonary vascular permeability. This review paper presents a refined model that they have proposed for decades describing the structural basis of endothelial barrier function.

Duran, W. N., Takenaka, H., and Hobson 2nd, R. W. (1998). Microvascular pathophysiology of skeletal muscle ischemia-reperfusion. Semin. Vasc. Surg. 11(3), 203-214. Dr. Joe Garcia and his colleagues have been studying the molecular mechanisms that regulate endothelial barrier funciton. This review paper presents a refined model that they have proposed for decades describing the structural basis of endothelial barrier.

Huxley, V. H., and Rumbaut, R. E. (2000). The micro vasculature as a dynamic regulator of volume and solute exchange. Clin. Exp. Pharmacol. Physiol. 27, 847-854.

Lum, H., and Malik, A. B. (1996). Mechanisms of increased endothelial permeability. Can. J. Physiol. Pharmacol. 74, 787-800. Dr. Asrar Malik's work has been focusing on the signal transduction in pulmonary microvascular endothelial hyperpermeability. This paper provides a thorough review on the signaling molecules that are involved in the modulation of endothelial permeability.

Michel, C. C., and Curry, F. E. (1999). Microvascular permeability. Physiol. Rev. 79, 703-761. This is a classic paper presenting important information on the physiological basis of microvascular exchange. The review covers both the physical and biochemical aspects of permeability regulation.

Shepro, D. (1988). Endothelial cells, inflammatory edema, and the microvascular barrier: Comments by a "free radical." Microvasc. Res. 35, 246-264.

van Nieuw Amerongen, G. P., and van Hinsbergh, V. W. M. (guest eds.) (2002). Special Issue: Endothelial hyperpermeability in vascular leakage. Vasc. Pharmacol. 39(4-5), 171-272. The entire issue discusses the molecular mechanisms of vascular endothelial hyperpermeability. It includes eight review articles by leading investigators in the field, addressing the signaling effects of calcium, Rho GTPases, tyrosine kinases, vascular endothelial growth factors, and interendothelial adhesion molecules as well as some pharmacological perspectives regarding the treatment of endothelial hyperpermeability.

Capsule Biography

Dr. Mack H. Wu is Associate Professor at University of California, Davis, School of Medicine, Department of Surgery. Previously he worked at the Texas A&M University Health Science Center, Department of Medical Physiology and Cardiovascular Research Institute led by Dr. Harris J. Granger. Dr Wu has been investigating the signaling mechanisms underlying the microvascular permeability response to growth factors and inflammatory stimuli. His research work is supported by the National Institute of Health.

Dr. Sarah Y. Yuan is Peal Stewart Professor and Director of Research at University of California at Davis School of Medicine, Department of Surgery. Previously, she worked as Professor and held the Raleigh White Chair of Surgery at the Texas A&M University Health Science Center. Dr. Yuan has been leading research programs focusing on the cellular and molecular control of microvascular barrier function in inflammation, trauma, sepsis, and diabetes. Her work is supported by the National Institute of Health, American Heart Association, and Scott & White Foundation.

Section E

Transport, Junctions, Adhesion Molecules

Chapter 46

Vesiculo-vacuolar Organelles Are Permeability Structures in the Endothelium of Normal and Tumor Microvessels

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