New View on Endothelial Cell Migration

Abstract

A ngiogenesis, the formation of new blood vessels from pre-existing ones, is essential during development and wound healing and in diseases, such as cancer. Invasion into and migration through the extracellular matrix (ECM) are mandatory for endothelial cells (ECs) to assemble a vascular system. Thus, there is tremendous interest in understanding the properties and behavior of ECs in 3-dimensional (3D) environments.The basic concepts underlying EC migration have mostly been gleaned from observations in 2D cell culture systems. 1,2 However, the 3D environment encountered in vivo is far more complex. Cells have to integrate and coordinate their adhesion with the ECM and interpret attractive and repulsive cues to choose their pathway. 3,4 Many studies in recent years have revealed that different cell types use specific mechanisms to migrate into and navigate through the ECM. Studies in primary human fibroblasts showed that structurally distinct 3D environments support different modes of cell migration and that the polarization of phosphatidylinositol (3,4,5)-triphosphate and Rho family GTPase signaling differs between lobopodia-and lamellipodia-based 3D migration. 5 Studies on leukocyte motility and cancer cell migration in 3D environments revealed a switch between adhesion-dependent mesenchymal (elongated) and adhesion-independent amoeboid (rounded) cell motility in these cell types. Adhesion-independent motility is driven by actin polymerization and actomyosin contraction. 6,7 Plasma membrane blebbing was once primarily viewed as a by-product of apoptotic and necrotic processes. However, subsequent studies showed that cell blebbing is not limited to the execution of cell death programs 8,9 but is also implicated in cell movement. Plasma membrane blebs are now accepted as one of the types of cell protrusions mediating migration, similar to filopodia, lamellipodia, invadopodia, and podosomes. 10 However, which types of migration occur in ECs and whether ECs can switch between them remain largely unknown.ECMs are major components of the body's connective tissue and influence cellular functions, in addition to acting as a major reservoir of releasable growth factors and peptide mediators. These matrices vary in terms of fiber thickness, density, and stiffness as well as the pore size between fibers. The main ECM component of interstitial tissues is fibrillar collagen type © 2016 American Heart Association, Inc. Objective-Cell-matrix interactions are crucial for regulating cellular activities, such as migration. This is of special importance for morphogenic processes, such as angiogenesis (the development of new blood vessels). Most of our understanding of cell migration relies on 2-dimensional (2D) experiments. However, the awareness that 3D settings might elicit different results has increased. Knowledge about endothelial cell (EC) behavior in 3D environments and the influence of matrix composition on EC migration, in particular, is still limited. Approach and Results-We characterize the migration of single E...

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