Angiogenesis is controlled by signals that stimulate motility in endothelial cells at the tips of vascular sprouts while maintaining cell-cell adhesion in the stalks of angiogenic sprouts. We show here that Gs-linked G protein-coupled receptor activation of cAMP-dependent protein kinase (PKA) plays an important role in regulating the switch between endothelial cell adhesion and migration by activating C-terminal Src kinase, leading to inhibition of pp60Src. Activated PKA blocks pp60Src-dependent vascular endot helial-cadherin phosphorylation, thereby stimulating cell-cell adhesion while suppressing endothelial cell polarization, motility, angiogenesis, and vascular permeability. Similar to the actions of Notch and Dll4, PKA activation blocks sprouting in newly forming embryonic blood vessels, while PKA inhibition promotes excessive sprouting in these vessels. These findings demonstrate that G protein-coupled receptors and PKA regulate vascular sprouting during angiogenesis by controlling endothelial cell migration and cell-cell adhesion through their actions on pp60Src.