The senescent secretome drives PLVAP expression in cultured human hepatic endothelia to promote monocyte transmigration

Liver sinusoidal endothelial cells (LSEC) undergo significant phenotypic change in chronic liver disease (CLD) and yet the factors that drive this process and the impact on their function as a vascular barrier and gatekeeper for immune cell recruitment are poorly understood. Plasmalemma vesicle-associated protein (PLVAP) has been characterised as a marker of LSEC in CLD, notably we found that PLVAP upregulation strongly correlated with markers of tissue senescence. Furthermore, exposure of human LSEC to the senescence associated secretory phenotype (SASP) led to a significant upregulation of PLVAP. Flow based assays demonstrated that SASP-driven leukocyte recruitment was characterised by paracellular transmigration of monocytes whilst the majority of lymphocytes migrated transcellularly. Knockdown studies confirmed that PLVAP selectively supported monocyte transmigration mediated through PLVAP’s impact on LSEC permeability by regulating Phospho-VE-cadherin expression and endothelial gap formation. PLVAP may therefore represent an endothelial target which selectively shapes the senescence-mediated immune microenvironment in liver disease.