The main focus of research in our laboratory is to understand the signaling mechanisms important for endothelial cell function. In blood vessels, endothelial cells normally form a continuous monolayer, which selectively restricts the passage of solutes and macromolecules to the surrounding tissue. Endothelial cell contraction and the disruption of endothelial cell-cell protein interactions results in increased monolayer permeability. Endothelial monolayer barrier dysfunction is involved in a variety of disease states, including arteriosclerosis, tumor metastasis, and acute lung injury.

Activation of protein kinase C (PKC), a serine-threonine kinase, is required for endothelial cell proliferation, migration, and differentiation into capillary tubules in vitro and angiogenesis in vivo. Direct activation of PKC increases endothelial monolayer permeability and disrupts cell-cell junction protein complexes. Non-specific pharmacological inhibitors of PKC block thrombin-, bradykinin-, and glucose-induced endothelial monolayer permeability, possibly by preventing the disruption of endothelial cell-cell junctions. Overexpression of selective PKC isoenzymes exerts distinct effects on endothelial permeability, proliferation, migration, and adhesion.

PKC is a family of twelve isoenzymes, each of which has discrete activators, cofactors, and substrates. Studies are in progress to determine whether selective PKC isoenzymes modulate endothelial monolayer permeability, proliferation, migration, and vessel formation by altering adherens junctions and/ or associated cytoplasmic proteins. A full understanding of the mechanism by which each PKC isoenzyme mediates endothelial cell function will require the identification of their selective downstream targets.