Endothelial Cell Heterogeneity: Earliest Findings to Present-Day Understanding

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DESCRIPTION: The endothelium, tissue which lines the myriad blood and lymphatic vessels of the body, was viewed for many years as a passive and monolithic tissue comprised of cells of a virtually undistinguishable nature. From the time of Wilhelm His naming of the endothelium in1865, there was little change in this view until the mid 20th century, when major structural differences such as tight junctions, fenestrations and sinusoidal organization were described. Beginning in the 1970s, as increasingly successful methods were developed for the culture of endothelial cells, new studies began to show that these cells, far from being homogeneous, manifested extensive heterogeneity, not only from organ to organ, but within individual organs, and even within a single vessel. Moreover, the endothelium, far from being passive and primarily dedicated to a barrier function, was a highly interactive tissue. For example, in the brain, endothelial cells provided enzymes essential for neuron activation. In lymph nodes, endothelial cells demonstrated exquisite cell surface specificity to permit recognition of specific subsets of circulating lymphocytes. When stimulated by inflammatory cytokines, endothelial cells became antigen-presenting cells. In wounds they promoted fibrin formation. Endothelial cells were found to vary in their response to growth factors, cytokine production, reaction to vasoactive substances, secretion of matrix products, and production of specific cell adhesion molecules, as well as in their affinity for specific tumor cells. No single endothelial cell prototype could serve any longer as a complete model for generalization. Moreover, in the last few years data from phage display analysis and gene arrays have made this complexity almost beyond understanding. Every new advance in technology has led to additional information about endothelial cells, but to a large extent critical connections between data obtained from different technologies at different times have only infrequently been attempted. To address endothelial cell heterogeneity in a meaningful manner will, in our opinion, require integration of the historical data obtained since the 19th century with the most recent data provided by proteomics and genomics, studies primarily carried out on discrete subpopulations of endothelial cells. It is this historical, integrative approach that we propose to use in preparing our treatise on endothelial cell heterogeneity.