Rac1 signaling facilitates vascular endothelial growth factor (VEGF)–stimulated angiogenesis. Engagement of its endothelial cell receptor VEGFR2 by VEGF induces phosphorylation of cytoplasmic tyrosines that initiate proangiogenic signaling and increases vascular permeability, in part by disrupting endothelial cell-cell junctions. Angiogenic responses induced by VEGF in vivo tend to be unstable unless a second signal is present, which can be provided by angiopoietin-1 (Ang1) binding to its signaling receptor Tie2 or by sphingosine 1-phosphate (S1P) binding to its G protein–coupled signaling receptors S1P1 or S1P3. Hoang and coworkers show that Tie2 and S1P1 signaling activates Rac1, and active Rac1 alters the endothelial cell–actin cytoskeleton and cell-cell junctions to decrease permeability of newly formed vessels in vitro and in vivo.¹  Previous studies have shown that Rac1 also activates endothelial cell NADPH oxidases (Nox) to produce reactive oxygen species that reversibly oxidize and inactivate protein tyrosine phosphatases (PTP) that limit the duration of proangiogenic signaling through VEGFR2. (Professional illustration by Paulette Dennis.)