Plasmalemma vesicle-associated protein (PLVAP), a cationic, endothelial-specific, integral membrane glycoprotein is exclusively localized to stomatal and fenestral diaphragms of caveolae, transendothelial channels and fenestrae. Fenestral and stomatal diaphragms are known to consist of radial fibrils which extend from the peripheral rim of the celllular pore and meet in a central mesh. They act as a permselective barrier, regulating permeability by allowing the passage of water and solutes but inhibiting the transfer of macromolecules across the endothelial barrier. It has been hypothesized that the radial fibrils of diaphragms are built by PLVAP dimers.
To learn about the molecular and biological functions of PLVAP, we generated mutant mice that are deficient in PLVAP and characterized their phenotype.
Depending on the respective genetic background, the deletion of Plvap caused either perinatal lethality associated with severe subcutaneous hemorrhages, edema, defects in vascular integrity, and cardiac malformations, or early postnatal death at around 4 weeks of age. Electron microscopy showed the complete absence of diaphragms in caveolae, transendothelial channels, and fenestrae in Plvap-deficient animals.
In addition, the lack of PLVAP caused a substantial reduction in the number of fenestrae in fenestrated vascular beds such as the choroid, the peritubular capillaries of the kidney interstitium, or the pancreas. The reduced number of fenestrae caused a restricted transendothelial passage of water and solutes, an effect which correlated with a retardation of postnatal growth.
Intriguingly, the deletion of PLVAP also caused lack of fenestrae in non-diaphragmed liver sinusoidal cells. Consequently, permeability and the passage of chylomicron remnants and other lipoproteins, such as HDL and LDL, was reduced between the lumen of liver sinusoids and the hepatocytes, a scenario that caused hyperlipoproteinemia and resulted in liver injury.
In conclusion, PLVAP was identified as an essential structural component of stomatal and fenestral diaphragms which are completely absent in endothelial cells of Plvap-deficient animals. Furthermore, PLVAP/diaphragms are required for the formation of fenestrations, since the loss of diaphragms due to the absence of PLVAP results in a dramatic reduction of fenestrations in both fenestrated and discontinuous vascular beds. This effect is accompanied by major physiological and metabolic changes such as in the liver where fenestrations in sinusoidal endothelial cells are critically required for the passage of lipoproteins
