PLVAP (plasmalemma vesicle-associated protein) is an endothelial cell-specific membrane protein essential for forming diaphragms that bridge endothelial fenestrae and regulate microvascular permeability 1. As the only known protein component of endothelial microdomains, PLVAP controls transendothelial channels and caveolar stomata, governing transcellular versus paracellular flow and the passage of water and solutes across different vascular beds 1. PLVAP expression marks distinct endothelial cell subtypes across tissues: in liver, PLVAP+ endothelial cells expand in cirrhosis and hepatocellular carcinoma within fibrotic and immunosuppressive microenvironments 23, while in pancreatic islets, PLVAP characterizes islet-specific endothelial cells with angiocrine functions 4. Beyond structural roles, PLVAP functions in regulating vascular permeability, leukocyte migration, and immune modulation 5. In heart failure, PLVAP+ endothelial cells associate with pro-inflammatory responses and fibrosis 6. Mechanistically, hepatic stellate cell-expressed PLVAP regulates fatty acid metabolism through PLVAP-diaphragmed caveolae along the sinusoidal lumen 7. PLVAP dysregulation is implicated in cancer, traumatic spinal cord injury, ischemic brain disease, and diabetic complications 1, positioning it as a potential therapeutic target across multiple pathologies.