The spatial patterning of the pro- and anti-angiogenic cues determine the site of angiogenesis and the fate conversion of tip cells. During the extension of sprouting vessels, tip cells sense not only VEGF signals, but also local mechanical properties and membrane tension with Piezo1 mechanosensitive channels on their branches, which collaboratively determine the extension/retraction of the branches and tip cell pathfinding. In the stabilized vessels, Piezo1 also senses the shear force from the blood flow and maintains vascular tone and function. VEGF, vascular growth factors; VEGFR, vascular growth factor receptors; RBC, red blood cell; EC, endothelial cell.