Small vessel disease (SVD) is a major cause of stroke, yet its molecular drivers remain elusive. ISD researchers now show that the stroke-risk gene FOXF2 is essential for maintaining healthy brain vessels by sustaining Tie2 signaling in endothelial cells. Loss of FOXF2 disrupted endothelial function, impaired blood–brain barrier integrity, and worsened outcomes after experimental stroke. Activating Tie2 with AKB-9778 rescued these deficits. The findings identify FOXF2–Tie2 signaling as a critical pathway in SVD and highlight a promising therapeutic target.