title: Using cultured endothelial cells to study endothelial barrier dysfunction: Challenges and opportunities.
abstract: Despite considerable progress in the understanding of endothelial barrier regulation and the identification of approaches that have the potential to improve endothelial barrier function, no drug- or stem cell-based therapy is presently available to reverse the widespread vascular leak that is observed in acute respiratory distress syndrome (ARDS) and sepsis. The translational gap suggests a need to develop experimental approaches and tools that better mimic the complex environment of the microcirculation in which the vascular leak develops. Recent studies have identified several elements of this microenvironment. Among these are composition and stiffness of the extracellular matrix, fluid shear stress, interaction of endothelial cells (ECs) with pericytes, oxygen tension, and the combination of toxic and mechanic injurious stimuli. Development of novel cell culture techniques that integrate these elements would allow in-depth analysis of EC biology that closely approaches the (patho)physiological conditions in situ. In parallel, techniques to isolate organ-specific ECs, to define EC heterogeneity in its full complexity, and to culture patient-derived ECs from inducible pluripotent stem cells or endothelial progenitor cells are likely to advance the understanding of ARDS and lead to development of therapeutics. This review 1) summarizes the advantages and pitfalls of EC cultures to study vascular leak in ARDS, 2) provides an overview of elements of the microvascular environment that can directly affect endothelial barrier function, and 3) discusses alternative methods to bridge the gap between basic research and clinical application with the intent of improving the translational value of present EC culture approaches.
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; Department of Pulmonary Diseases, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; j.aman@vumc.nl.
authors.forename: Jurjan
authors.initials: J
authors.lastname: Aman
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Ester M
authors.initials: EM
authors.lastname: Weijers
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Geerten P
authors.initials: GP
authors.lastname: van Nieuw Amerongen
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Victor W M
authors.initials: VW
authors.lastname: van Hinsbergh
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D002450:Cell Communication; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology / Q000503:physiopathology*; D005109:Extracellular Matrix / Q000502:physiology; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000473:pathology; D046210:Microfluidic Analytical Techniques; D012128:Respiratory Distress Syndrome / Q000473:pathology* / Q000503:physiopathology
keywords: acute respiratory distress syndrome; cell culture; endothelial barrier