Evolving functions of endothelial cells in inflammation

Endothelial cells are major participants in and regulators of inflammatory reactions.Resting endothelial cells prevent coagulation, control blood flow and passage of proteins from blood into tissues, and inhibit inflammation. Production of nitric oxide (NO) has a role in these processes and inadequate production of NO is a major cause of endothelial cell dysfunction.Type I activation of endothelial cells mediated by G-protein coupled receptors (GPCRs) that activate G-protein αq subunits and cause endothelial cells to increase blood flow (enhancing delivery of leukocytes to the tissue), increase leakage of plasma proteins into the tissue (creating a provisional matrix to support leukocytes) and promote the binding and activation of neutrophils, encouraging their extravasation into an inflammatory site. Type I activation responses are rapid, independent of protein synthesis, and transient, spontaneously shutting off within 10–20 minutes.Type II activation of endothelial cells mediated by pro-inflammatory cytokines such as tumour-necrosis factor (TNF) and interleukin-1 (IL-1) also increase local blood flow, leakage of plasma proteins and recruit leukocytes. Type II activation responses depend on new gene transcription and protein translation, and are slower in onset but more sustained than type I activation responses, lasting for hours to days.Type-II-activated endothelial cells spontaneously evolve from a phenotype that recruits neutrophils to one that recruits monocytes and T cells. Polarizing cytokines, such as interferon-γ or IL-4 can further modify the activated endothelial cell phenotype to preferentially support T helper 1 (TH1)-cell- or TH2-cell-type inflammatory reactions, respectively.In chronic inflammation, endothelial cells respond to angiogenic factors, such as vascular endothelial growth factor A (VEGFA), to form new blood vessels that are required to sustain an inflammatory neo-tissue such as a pannus in rheumatoid arthritis. Endothelial cells may also respond to lymphotoxin-β to acquire characteristics of high endothelial venules and support the development of tertiary lymphoid organs.Many inflammatory processes display both acute and chronic changes at the same time. This may result because mediators of acute inflammation (such as TNF) contribute to the phenotypes of endothelial cells associated with chronic inflammatory and, similarly mediators of chronic inflammation (such as VEGFA) may also contribute to endothelial cell behaviours associated with acute inflammation.Many therapeutic agents thought to target inflammatory processes or vascular processes affect the inflammatory function of endothelial cells. Our deeper understanding of the mediators, signals and effector molecules involved in endothelial cell inflammatory functions may allow specific targeting of this cell type as a treatment for inflammatory diseases.