Mack H. Wu and Sarah Y. Yuan

University of California School of Medicine, Sacramento, CA

Blood-tissue exchange occurs in the downstream segments of microvasculature, namely capillary and postcapillary venules. The wall of these exchange microvessels consists of a sheet of cells, endothelial cells, which connect to each other with closely opposed intercellular junctions. This endothelial sheet is tethered to a network of extracellular matrices in the basement membrane, forming a barrier structure that controls the transvascular movement of blood components. The permeability of microvascular endothe-lium is maintained by an equilibrium between the contractile force generated at the endothelial cytoskeleton and the adhesive forces produced at endothelial cell-cell junctions and cell-matrix focal contacts (Figure 1). A dynamic interaction among these structural elements controls the opening and closing of the paracellular pathways for fluid and cells to move across the vessel wall and thus serves as a fundamental mechanism in the physiological and pathological regulation of blood-tissue exchange.

Aberrations of microvascular barrier function lead to an abnormal extravasation of blood components, resulting in tissue edema and dysfunction. This cellular process is involved in inflammation, ischemia-reperfusion injury, trauma, sepsis, diabetes, and atherosclerosis. Under such disease conditions, many inflammatory mediators are released, and most of them possess a potent permeability-increasing effect. These mediators, including histamine, bradykinin, platelet activating factor, growth factors, glyca-tion products, cytokines, reactive oxygen species, and activated leukocytes, can interact with the microvascular endothelium and activate an array of intracellular second messengers, which in turn catalyze a series of biochemical reactions at the endothelial cytoskeleton and cell-cell and cell-matrix adhesive structures (Figure 2). Ultimately, endothelial cells contract or undergo conformational changes, resulting in endothelial hyperpermeability and microvascular barrier dysfunction.

Protein kinases, classified as serine/threonine kinases or tyrosine kinases based on their substrate specificity, constitute an important category of intracellular second messengers that mediate the structural and functional changes occurring in the endothelium under physiological conditions as well as during inflammatory stimulation. Several groups of protein kinases have been characterized and their involvement in the cellular response to inflammation or injury has been documented. The following discussion focuses on the protein kinases that are frequently implicated in the modulation of microvascular permeability.

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