Abstract-Endothelial cell migration is essential to angiogenesis. This motile process is directionally regulated by chemotactic, haptotactic, and mechanotactic stimuli and further involves degradation of the extracellular matrix to enable progression of the migrating cells. It requires the activation of several signaling pathways that converge on cytoskeletal remodeling. Then, it follows a series of events in which the endothelial cells extend, contract, and throw their rear toward the front and progress forward. The aim of this review is to give an integrative view of the signaling mechanisms that govern endothelial cell migration in the context of angiogenesis. (Circ Res. 2007;100:782-794.)Key Words: endothelial cells Ⅲ chemotaxis Ⅲ haptotaxis Ⅲ mechanotaxis Ⅲ migration Ⅲ angiogenesis Ⅲ VEGF Ⅲ integrins Ⅲ actin Ⅲ remodeling E ndothelial cells derive from the successive differentiation of mesodermal cells into hemangioblasts, which leads to the formation of the first vascular structures that are called primitive blood islands. The hemangioblasts from the center of the islands give rise to the hematopoietic stem cells, whereas the peripheral hemangioblasts differentiate into angioblasts, the precursors of mature endothelial cells. Under the influence of vascular endothelial growth factor (VEGF), the angioblasts and newly formed endothelial cells migrate on a matrix constituted mainly of collagen and hyaluronan, allowing the fusion of the blood islands, their remodeling into tubular structures, and the formation of the first primitive vascular plexus. These tubules remodel through vasculogenesis into larger vessels, leading to vascularization of the embryo. 1 In contrast to vasculogenesis, angiogenesis refers to the formation of new blood vessels from preexisting ones ( Figure 1). It is required in many physiological and pathological conditions, including embryonic development, wound healing, tissue regeneration, and tumor growth. The process is regulated by a tight balance between pro-and antiangiogenic agents and involves a cascade of events of which migration of capillary endothelial cells is an essential component. 2 The basic concepts of the cellular and molecular machinery underlying endothelial cell migration have been obtained mostly from observations of cell culture systems (see the online data supplement, available at http://circres.ahajournals.org). However, the 3D environment within a whole organism is far more complex, and the cells must move between and among other cells while they interpret attractive and repulsive cues to choose their path. They must integrate and coordinate their adhesion with their surroundings and sense when to start and stop moving. Genetic dissection using in particular zebrafish 3,4 and mouse embryo 5 now offers the possibility to understand endothelial cell migration in a physiological context. The aim of this review is to make an integrative update on the signaling and physiological aspects of endothelial cell migration in angiogenesis.Original received October 18, 200...