Plasmalemma vesicle-associated protein (PLVAP) is an endothelial-associated protein involved in endothelial diaphragm formation and maintenance of basal vascular permeability. At the same time, PLVAP has roles in immunity by facilitating leukocyte diapedesis at inflammatory sites and controlling peripheral lymph node morphogenesis and the entry of soluble antigens into lymph node conduits. Structurally, PLVAP forms sieve-like diaphragms across fenestral pores and caveolae, acting as a size-selective barrier. PLVAP deficiency in mice leads to complete loss of endothelial diaphragms, resulting in severe vascular leakage, impaired immune cell trafficking, and neonatal lethality, underscoring its essential role in both vascular and immune functions.