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Patterning of functional blood vessel networks is achieved by pruning of superfluous connections. The cellular and molecular principles of vessel regression are poorly understood. Here we show that regression is mediated by dynamic and polarized migration of endothelial cells, representing anastomosis in reverse. Establishing and analyzing the first axial polarity map of all endothelial cells in a remodeling vascular network, we propose that balanced movement of cells maintains the primitive plexus under low shear conditions in a metastable dynamic state. We predict that flow-induced polarized migration of endothelial cells breaks symmetry and leads to stabilization of high flow/shear segments and regression of adjacent low flow/shear segments., A study of mouse retina and zebrafish vasculature shows how differential blood flow patterns direct the orientation and migration of endothelial cells as a mechanism for stabilizing or pruning individual blood vessel segments., Author Summary The question of how blood vessel networks achieve their branching patterns is key to our understanding of organ formation as well as diseases that involve vascular anomalies. Regression (or pruning) of blood vessel segments is required for functional vascular branching patterns; however, the molecular basis for this is poorly understood. Here we investigate remodeling of vascular networks in the mouse retina and in zebrafish and focus on the cellular components of the endothelium—the cell layer that lines blood vessels. We use high-resolution imaging to map and analyze endothelial cell orientation in relation to blood flow direction during vascular remodeling. We identify sequential steps that characterize blood vessel regression through endothelial cell migration, finding no evidence for predicted endothelial cell death in the retina. Combining endothelial cell mapping with computational modeling of flow-induced shear forces allows a systems-level prediction of endothelial cell migration patterns that drive vascular remodeling. Our work establishes how local differences in blood flow drive endothelial cells to orientate and migrate against the direction of flow. We show that the dynamic and polarized migration of endothelial cells leads to the regression of segments under low flow and the stabilization of segments under high flow. We propose that strong flow functions as an “attractor” for endothelial cells, while poorly perfused vessels are less “attractive,” thereby promoting regression of non-functional vessel segments.