The biomechanical properties of endothelial cells are critically important for multiple endothelial cell functions including permeability, extravasation of immune cells, migration, and angiogenesis. From a biomechanical standpoint, the two primary parameters are the deformability of the cell and the fluid properties of its plasma membrane.(The terms ‘‘deformability’’and ‘‘fluid properties’’are used extensively in the literature and, as applied to plasma membranes, they have specific meanings. The term ‘‘deformability’’is typically taken to mean ‘‘elastic modulus’’, a property that is measured using AFM, with the modulus being extracted from the data using the Hertz model. The term ‘‘fluid properties’’or ‘‘fluidity’’is typically taken to mean the viscosity of the plasma membrane, a property determined from the diffusion constant (either rotational or translational) of a membrane constituent.) These two parameters, which are determined by two different cellular structures, the F-actin network and the plasma membrane, cannot be controlled independently because of the complex and still evolving understanding of the interactions between them. While it may be tempting to start with the assumption that the plasma membrane simply rides on the cytoskeletal structure, this is not the case, and Levitan and co-workers (1–3) have pioneered the effort to elucidate the subtle and complex molecular interactions responsible for this codependency.

The two properties of cell deformability and membrane fluidity play complementary roles in immune cell extravasation and other permeabilityrelated functions in endothelial cells, as is schematized in Fig. 1. While gaining systematic structural control over cytoskeletal rigidity poses a substantial challenge, the plasma membrane, in contrast, is amenable to facile changes in composition, either by exposure to constituents or by the action of enzymes (eg, acid sphingomyelinase conversion of sphingomyelin to ceramide)(4, 5), or by oxidation of selected species, as is considered in the latest work from the Levitan group (Ayee et al.(6)). Indeed, exploring the ability to control interactions between the plasma membrane and the cytoskeletal structure through the composition of the plasma membrane is at once a promising avenue and an exceptionally complex effort owing to the compositional heterogeneity of the membrane and the limited extent to which the interactions between these two cellular entities are understood.