CDH5 (VE-cadherin) is a calcium-dependent cell adhesion protein essential for endothelial cell function and vascular integrity. Primary function: CDH5 mediates homophilic cell-cell adhesion in endothelial cells and controls intercellular junction cohesion and organization 1. Mechanism: CDH5 associates with alpha-catenin to link junctions to the cytoskeleton 2 and couples actin fibers to cell junctions via AMOTL2 and MAGI1. It works with KRIT1 and PALS1 to establish endothelial polarity and vascular lumen through Par polarity complex and RAP1B activation 3. CDH5 positively regulates actin stress fiber reorientation and endothelial cell mechanotransduction 4. Disease relevance: CDH5 dysfunction contributes to blood-brain barrier leakage during aging through NAD+-dependent mitochondrial dysfunction 5. In cardiovascular disease, endothelial cells undergo transient mesenchymal activation after myocardial infarction via Cdh5+ lineage transitions 6. Endothelial CDH5+ cells display plasticity in atrial fibrosis, with mesenchymal-activated endothelial cells promoting fibroblast proliferation through TGF-β1 7. Clinical significance: CDH5 is a critical marker identifying endothelial cell populations in genetic lineage tracing studies and a target for understanding vascular aging and fibrotic diseases. Pharmacological approaches targeting associated NAD+ pathways or endothelial-specific signaling may offer therapeutic strategies for age-related vascular dysfunction and fibrosis-related pathologies.